Selected CGRP-antagonists, process for preparing them and their use as pharmaceutical compositions

ABSTRACT

The present invention relates to the CGRP antagonists of general formula 
                         
wherein A, X, D, E, G, M, Q and R 1  to R 3  are defined as in claim  1,  the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates thereof, the mixtures thereof and the salts thereof and the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids, pharmaceutical compositions containing these compounds, the use thereof and processes for the preparation thereof.

FIELD OF THE INVENTION

The present invention relates to the CGRP-antagonists of general formula

wherein A, D, E, G, M, Q, X, R¹, R² and R³ are defined as below, thetautomers, the isomers, the diastereomers, the enantiomers, the hydratesthereof, the mixtures thereof and the salts thereof as well as thehydrates of the salts, particularly the physiologically acceptable saltsthereof with inorganic or organic acids or bases, pharmaceuticalcompositions containing these compounds, the use thereof and processesfor the preparation thereof.

In the above general formula (I) in a first embodiment

A denotes an oxygen or sulphur atom,

X denotes an oxygen or sulphur atom,

(a) D, E independently of one another in each case denote a methynegroup or the nitrogen atom and

-   -   G denotes a methyne group substituted by the group R^(a),    -   M denotes a methyne group substituted by the group R^(b),    -   Q denotes a methyne group substituted by the group R^(c),        -   while one or two of the groups G. M and Q in each case may            also represent a nitrogen atom,

or

(b) D and E in each case denote a methyne group, while one of the groupsD and E may also represent a nitrogen atom, and

-   -   G, M and Q in each case denote a nitrogen atom,

while R^(a), R^(b) and R^(c) independently of one another in each casedenote a hydrogen or halogen atom, a C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, cyclo-C₃₋₇-alkyl, cyclo-C₃₋₇-alkenyl, cyano, hydroxy,hydroxy-C₁₋₆-alkyl, hydroxy-C₃₋₆-alkenyl, hydroxy-C₃₋₆-alkynyl,C₁₋₆-alkoxy, C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkoxy-C₃₋₆-alkenyl,C₁₋₆-alkoxy-C₃₋₆-alkynyl, C₃₋₆-alkenoxy-C₁₋₆-alkyl,C₃₋₆-alkenoxy-C₃₋₆-alkenyl, C₃₋₆-alkenoxy-C₃₋₆-alkynyl,C₃₋₆-alkynoxy-C₁₋₆-alkyl, C₃₋₆-alkynoxy-C₃₋₆-alkenyl,C₃₋₆-alkynoxy-C₃₋₆-alkynyl, thiohydroxy, C₁₋₆-alkylthio,C₃₋₆-alkenylthio, C₃₋₆-alkynylthio, amino, C₁₋₆-alkyl-amino,C₃₋₆-alkenyl-amino, C₃₋₆-alkynyl-amino, di-(C₁₋₆-alkyl)-amino,di-(C₃₋₆-alkenyl)-amino, di-(C₃₋₆-alkynyl)-amino, amino-C₁₋₆-alkyl,C₁₋₃-alkyl-amino-C₁₋₆-alkyl, di(C₁₋₃-alkyl)-amino-C₁₋₆-alkyl,amino-C₃₋₆-alkenyl, C₁₋₃-alkyl-amino-C₃₋₆-alkenyl,di-(C₁₋₃-alkyl)-amino-C₃₋₆-alkenyl, amino-C₃₋₆-alkynyl,C₁₋₃-alkyl-amino-C₃₋₆-alkynyl, di-(C₁₋₃-alkyl)-amino-C₃₋₆-alkynyl,hydroxycarbonyl, phenylcarbonyl, pyridylcarbonyl, C₁₋₆-alkyl-carbonyl,C₂₋₆-alkenyl-carbonyl, C₂₋₆-alkynyl-carbonyl, formyl,C₁₋₆-alkoxy-carbonyl, C₃₋₆-alkenoxy-carbonyl, C₃₋₆-alkynoxy-carbonyl,aminocarbonyl, C₁₋₆-alkyl-aminocarbonyl, C₃₋₆-alkenyl-aminocarbonyl,C₃₋₆-alkynyl-aminocarbonyl, di-(C₁₋₆-alkyl)-aminocarbonyl,di-(C₃₋₆-alkenyl)-aminocarbonyl, di-(C₃₋₆-alkynyl)-aminocarbonyl,formylamino, C₁₋₆-alkyl-carbonylamino, C₂₋₆-alkenyl-carbonylamino,C₂₋₆-alkynyl-carbonylamino, formyl-C₁₋₆-alkyl-amino,formyl-C₃₋₆-alkenyl-amino, formyl-C₃₋₆-alkynyl-amino,C₁₋₆-alkyl-carbonyl-C₁₋₆-alkyl-amino,C₂₋₆-alkenyl-carbonyl-C₁₋₆-alkyl-amino,C₂₋₆-alkynyl-carbonyl-C₁₋₆-alkyl-amino,C₁₋₆-alkyl-carbonyl-C₃₋₆-alkenyl-amino,C₂₋₆-alkenyl-carbonyl-C₃₋₆-alkenyl-amino,C₂₋₆-alkynyl-carbonyl-C₃₋₆-alkenyl-amino,C₁₋₆-alkyl-carbonyl-C₃₋₆-alkynyl-amino,C₂₋₆-alkenyl-carbonyl-C₃₋₆-alkynyl-amino,C₂₋₆-alkynyl-carbonyl-C₃₋₆-alkynyl-amino, C₁₋₆-alkyl-sulphonyl,C₂₋₆-alkenyl-sulphonyl, C₂₋₆-alkynyl-sulphonyl, C₁₋₆-alkyl-sulphinyl,C₂₋₆-alkenyl-sulphinyl, C₂₋₆-alkynyl-sulphinyl,C₁₋₆-alkyl-sulphonylamino, C₂₋₆-alkenyl-sulphonylamino,C₂₋₆-alkynyl-sulphonylamino, C₁₋₆-alkyl-sulphonyl-C₁₋₆-alkylamino,C₁₋₆-alkyl-sulphonyl-C₃₋₆-alkenylamino,C₁₋₆-alkyl-sulphonyl-C₃₋₆-alkynylamino,C₂₋₆-alkenyl-sulphonyl-C₁₋₆-alkylamino,C₂₋₆-alkenyl-sulphonyl-C₃₋₆-alkenylamino,C₂₋₆-alkenyl-sulphonyl-C₃₋₆-alkynylamino,C₂₋₆-alkynyl-sulphonyl-C₁₋₆-alkylamino,C₂₋₆-alkynyl-sulphonyl-C₃₋₆-alkenylamino,C₂₋₆-alkynyl-sulphonyl-C₃₋₆-alkynylamino, aminosulphonyl,C₁₋₆-alkylaminosulphonyl, di-(C₁₋₆-alkyl)-aminosulphonyl,C₃₋₆-alkenylaminosulphonyl, di-(C₃₋₆-alkenyl)-aminosulphonyl,C₃₋₆-alkynylaminosulphonyl or di-(C₃₋₆-alkynyl)-aminosulphonyl group

-   -   with the provisos that, if none of the groups D, E, G, M and Q        denotes a nitrogen atom,    -   (i) R^(a) does not denote a hydrogen atom, if both R^(b) and        R^(c) in each case denote a C₁₋₆-alkyl group,    -   (ii) R^(c) does not denote a hydrogen atom if both R^(a) and        R^(b) in each case denote a C₁₋₆-alkyl group,    -   (iii) R^(a) does not take on the meanings of a hydrogen,        fluorine, chlorine, bromine or iodine atom or a difluoro- or        trifluoromethyl group if R^(c) denotes a C₁₋₆-alkyl,        C₂₋₆-alkenyl or C₂₋₆-alkynyl group and R^(b) denotes a chlorine        or bromine atom, an amino, methylamino or hydroxy group,    -   (iv) R^(c) does not take on the meanings of a hydrogen,        fluorine, chlorine, bromine or iodine atom or a difluoro- or        trifluoromethyl group if R^(a) denotes a C₁₋₆-alkyl,        C₂₋₆-alkenyl or C₂₋₆-alkynyl group and R^(b) denotes a chlorine        or bromine atom, an amino, methylamino or hydroxy group,

R¹ denotes a saturated, mono- or diunsaturated 5- to 7-membered aza,diaza, triaza, oxaza, thiaza, thiadiaza or S,S-dioxido-thiadiazaheterocycle,

-   -   while the above-mentioned heterocycles are linked to the        piperidine ring in formula I via a carbon or nitrogen atom or    -   are spirocyclically linked to the piperidine ring in formula I        via two carbon atoms, via a carbon and a nitrogen atom, via a        carbon and an oxygen atom or via a carbon and a sulphur atom,    -   contain one or two carbonyl or thiocarbonyl groups adjacent to a        nitrogen atom,    -   may be substituted at one of the nitrogen atoms by a C₁₋₆-alkyl,        C₃₋₆-alkenyl or C₃₋₆-alkenyl group,    -   may be substituted at one or at two carbon atoms by a        C₁₋₆-alkyl, C₂₋₆-alkenyl or C₂₋₆-alkynyl group, by a phenyl,        phenylmethyl, naphthyl, biphenylyl, pyridinyl, diazinyl, furyl,        thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl,        pyrazolyl, 1-(C₁₋₃-alkyl)-pyrazolyl, imidazolyl or        1-(C₁₋₃-alkyl)-imidazolyl group, while the substituents may be        identical or different, and    -   an olefinic double bond of one of the above-mentioned        unsaturated heterocycles may be fused to a phenyl, naphthyl,        pyridine, diazine, 1,3-oxazole, thienyl, furan, thiazole,        pyrrole, N—C₁₋₃-alkyl-pyrrole or quinoline ring, to a        1H-quinolin-2-one ring optionally substituted at the nitrogen        atom by a C₁₋₆-alkyl, C₃₋₆-alkenyl or C₃₋₆-alkynyl group or to        an imidazole or N-C₁₋₃-alkyl-imidazole ring or else two olefinic        double bonds of one of the above-mentioned unsaturated        heterocycles may each be fused to a phenyl or pyridine ring,        -   while the phenyl, pyridinyl, diazinyl, furyl, thienyl,            pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl,            pyrazolyl, 1-C₁₋₃-alkyl-pyrazolyl, imidazolyl or            1-C₁₋₃-alkyl-imidazolyl groups contained in R¹ and benzo-,            thieno-, pyrido- and diazino-fused heterocycles in the            carbon skeleton may additionally be mono-, di- or            trisubstituted by halogen atoms, C₁₋₆-alkyl, C₂₋₆-alkenyl,            C₂₋₆-alkynyl, cyclo-C₃₋₇-alkyl, cyclo-C₃₋₇-alkenyl, cyano,            hydroxy, hydroxy-C₁₋₆-alkyl, hydroxy-C₃₋₆-alkenyl,            hydroxy-C₃₋₆-alkynyl, C₁₋₆-alkoxy, C₁₋₆-alkoxy-C₁₋₆-alkyl,            C₁₋₆-alkoxy-C₃₋₆-alkenyl, C₁₋₆-alkoxy-C₃₋₆-alkynyl,            C₃₋₆-alkenoxy-C₁₋₆-alkyl, C₃₋₆-alkenoxy-C₃₋₆-alkenyl,            C₃₋₆-alkenoxy-C₃₋₆-alkynyl, C₃₋₆-alkynoxy-C₁₋₆-alkyl,            C₃₋₆-alkynoxy-C₃₋₆-alkenyl, C₃₋₆-alkynoxy-C₃₋₆-alkynyl,            thiohydroxy, C₁₋₆-alkylthio, C₃₋₆-alkenylthio,            C₃₋₆-alkynylthio, amino, C₁₋₆-alkyl-amino,            C₃₋₆-alkenyl-amino, C₃₋₆-alkynyl-amino,            di-(C₁₋₆-alkyl)-amino, di-(C₃₋₆-alkenyl)-amino,            di-(C₃₋₆-alkynyl)-amino, amino-C₁₋₆-alkyl,            C₁₋₃-alkyl-amino-C₁₋₆-alkyl,            di-(C₁₋₃-alkyl)-amino-C₁₋₆-alkyl, amino-C₃₋₆-alkenyl,            C₁₋₃-alkyl-amino-C₃₋₆-alkenyl,            di-(C₁₋₃-alkyl)-amino-C₃₋₆-alkenyl, amino-C₃₋₆-alkynyl,            C₁₋₃-alkyl-amino-C₃₋₆-alkynyl,            di-(C₁₋₃-alkyl)-amino-C₃₋₆-alkynyl, hydroxycarbonyl,            phenylcarbonyl, pyridylcarbonyl, C₁₋₆-alkyl-carbonyl,            C₂₋₆-alkenyl-carbonyl, C₂₋₆-alkynyl-carbonyl, formyl,            C₁₋₆-alkoxy-carbonyl, C₃₋₆-alkenoxy-carbonyl,            C₃₋₆-alkynoxy-carbonyl, aminocarbonyl,            C₁₋₆-alkyl-aminocarbonyl, C₃₋₆-alkenyl-aminocarbonyl,            C₃₋₆-alkynyl-aminocarbonyl, di-(C₁₋₆-alkyl)-aminocarbonyl,            di-(C₃₋₆-alkenyl)-aminocarbonyl,            di-(C₃₋₆-alkynyl)-aminocarbonyl, formylamino,            C₁₋₆-alkyl-carbonylamino, C₂₋₆-alkenyl-carbonylamino,            C₂₋₆-alkynyl-carbonylamino, formyl-C₁₋₆-alkyl-amino,            formyl-C₃₋₆-alkenyl-amino, formyl-C₃₋₆-alkynyl-amino,            C₁₋₆-alkyl-carbonyl-C₁₋₆-alkyl-amino,            C₂₋₆-alkenyl-carbonyl-C₁₋₆-alkyl-amino,            C₂₋₆-alkynyl-carbonyl-C₁₋₆-alkyl-amino,            C₁₋₆-alkyl-carbonyl-C₃₋₆-alkenyl-amino,            C₂₋₆-alkenyl-carbonyl-C₃₋₆-alkenyl-amino,            C₂₋₆-alkynyl-carbonyl-C₃₋₆-alkenyl-amino,            C₁₋₆-alkyl-carbonyl-C₃₋₆-alkynyl-amino,            C₂₋₆-alkenyl-carbonyl-C₃₋₆-alkynyl-amino,            C₂₋₆-alkynyl-carbonyl-C₃₋₆-alkynyl-amino,            C₁₋₆-alkyl-sulphonyl, C₂₋₆-alkenyl-sulphonyl,            C₂₋₆-alkynyl-sulphonyl, C₁₋₆-alkyl-sulphinyl,            C₂₋₆-alkenyl-sulphinyl, C₂₋₆-alkynyl-sulphinyl,            C₁₋₆-alkyl-sulphonylamino, C₂₋₆-alkenyl-sulphonylamino,            C₂₋₆-alkynyl-sulphonylamino,            C₁₋₆-alkyl-sulphonyl-C₁₋₆-alkylamino,            C₁₋₆-alkyl-sulphonyl-C₃₋₆-alkenylamino,            C₁₋₆-alkyl-sulphonyl-C₃₋₆-alkynylamino,            C₂₋₆-alkenyl-sulphonyl-C₁₋₆-alkylamino,            C₂₋₆-alkenyl-sulphonyl-C₃₋₆-alkenylamino,            C₂₋₆-alkenyl-sulphonyl-C₃₋₆-alkynylamino,            C₂₋₆-alkynyl-sulphonyl-C₁₋₆-alkylamino,            C₂₋₆-alkynyl-sulphonyl-C₃₋₆-alkenylamino,            C₂₋₆-alkynyl-sulphonyl-C₃₋₆-alkynylamino, aminosulphonyl,            C₁₋₆-alkylaminosulphonyl, di-(C₁₋₆-alkyl)-aminosulphonyl,            C₃₋₆-alkenylaminosulphonyl,            di-(C₃₋₆-alkenyl)-aminosulphonyl,            C₃₋₆-alkynylaminosulphonyl, di-(C₃₋₆-alkynyl)-aminosulphonyl            groups, while the substituents may be identical or different            and    -   the double and triple bonds of the C₃₋₆-alkenyl or C₃₋₆-alkynyl        groups contained in the groups given as definitions for R^(a),        R^(b), R^(c) and R¹ hereinbefore may be isolated from any        heteroatoms optionally also contained in these groups,

R² denotes the hydrogen atom,

a phenylmethyl group or a C₂₋₇-alkyl group which may be substituted inthe ω position by a cyclo-C₃₋₇-alkyl, cyclo-C₃₋₇-alkenyl, phenyl,pyridinyl, diazinyl, hydroxy, amino, C₁₋₆-alkylamino,di-(C₁₋₆-alkyl)-amino, C₃₋₆-alkenylamino, di-(C₃₋₆-alkenyl)amino,C₃₋₆-alkynylamino, di-(C₃₋₆-alkynyl)amino, hydroxycarbonyl,C₁₋₆-alkoxycarbonyl, aminocarbonyl, aminocarbonylamino,C₁₋₆-alkylcarbonylamino, C₂₋₆-alkenylcarbonylamino,C₂₋₆-alkynylcarbonylamino, 4-morpholinyl, [bis-(2-hydroxyethyl)]amino,4-(C₁₋₆-alkyl)-1-piperazinyl or 4-(ω-hydroxy-C₂₋₇-alkyl)-1-piperazinylgroup,

a phenyl or pyridinyl group,

-   -   while the phenyl, pyridinyl and diazinyl groups mentioned in the        groups defined hereinbefore for R² or contained as substituents        may additionally be mono-, di- or trisubstituted in the carbon        skeleton by halogen, by C₁₋₃-alkyl, C₂₋₃-alkenyl, C₂₋₃-alkynyl,        C₁₋₃-alkoxy, hydroxy, amino, C₁₋₃-alkylamino,        di-(C₁₋₃-alkyl)-amino, amino-C₁₋₃-alkyl,        C₁₋₃-alkyl-amino-C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl,        C₁₋₃-alkyl-carbonylamino, C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl,        aminocarbonyl, C₁₋₃-alkyl-aminocarbonyl,        di-(C₁₋₃-alkyl)-aminocarbonyl, cyano, aminosulphonyl,        C₁₋₃-alkyl-aminosulphonyl, di-(C₁₋₃-alkyl)-aminosulphonyl,        C₁₋₃-alkyl-thio, C₁₋₃-alkyl-sulphinyl or C₁₋₃-alkyl-sulphonyl        and the substituents may be identical or different,

R³ denotes the hydrogen atom or a C₁₋₃-alkyl group substituted by aphenyl or pyridinyl group,

-   -   while the C₁₋₃-alkyl group may be connected to an alkyl group        contained in R² or to a phenyl or pyridyl ring contained in R²        including the nitrogen atom to which R² and R³ are bound,        forming a 4- to 7-membered ring,

or

R² and R³ together with the enclosed nitrogen atom denote a group ofgeneral formula

wherein

-   -   Y¹ denotes the carbon atom or, if R⁵ denotes a pair of free        electrons, it may also denote the nitrogen atom,    -   q and r, if Y¹ denotes the carbon atom, denote the numbers 0, 1        or 2, or    -   q and r, if Y¹ denotes the nitrogen atom, denote the numbers 1        or 2,    -   R⁴ denotes the hydrogen atom, an amino, C₁₋₄-alkyl-amino,        di-(C₁₋₄-alkyl)-alkylamino, C₁₋₆-alkyl, a cyclo-C₃₋₇-alkyl or        cyclo-C₃₋₇-alkenyl group optionally substituted by a        hydroxycarbonyl, C₁₋₆-alkoxycarbonyl, hydroxycarbonyl-C₁₋₃-alkyl        or C₁₋₆-alkoxycarbonyl-C₁₋₃-alkyl group, an amino-C₂₋₇-alkyl,        C₁₋₄-alkyl-amino-C₂₋₇-alkyl, di-(C₁₋₄-alkyl-amino)-C₂₋₇-alkyl,        aminoiminomethyl, aminocarbonylamino,        C₁₋₄-alkyl-aminocarbonylamino,        di-(C₁₋₄-alkyl)-aminocarbonylamino,        C₁₋₄-alkyl-aminocarbonyl-C₁₋₄-alkyl-amino,        di-(C₁₋₄-alkyl)-aminocarbonyl-C₁₋₄-alkyl-amino,        phenylaminocarbonylamino, aminocarbonyl,        C₁₋₄-alkyl-aminocarbonyl, di-(C₁₋₄-alkyl)-aminocarbonyl,        aminocarbonyl-C₁₋₃-alkyl, C₁₋₄-alkyl-aminocarbonyl-C₁₋₃-alkyl,        di-(C₁₋₄-alkyl)-aminocarbonyl-C₁₋₃-alkyl,        aminocarbonylamino-C₁₋₃-alkyl, C₁₋₆-alkoxycarbonyl,        C₃₋₆-alkenoxycarbonyl, C₃₋₆-alkynoxycarbonyl,        C₁₋₆-alkoxycarbonyl-C₁₋₃-alkyl,        C₁₋₆-alkenoxycarbonyl-C₁₋₃-alkyl,        C₁₋₆-alkynoxycarbonyl-C₁₋₃-alkyl or hydroxycarbonyl-C₁₋₃-alkyl        group,    -   a phenyl, pyridinyl, diazinyl, 1-naphthyl, 2-naphthyl,        pyridinylcarbonyl or phenylcarbonyl group which may be mono-,        di- or trisubstituted in each case in the carbon skeleton by        halogen, by C₁₋₃-alkyl, C₂₋₃-alkenyl, C₂₋₃-alkynyl, C₁₋₃-alkoxy,        hydroxy, amino, C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)-amino,        amino-C₁₋₃-alkyl, C₁₋₄-alkyl-amino-C₁₋₃-alkyl,        di-(C₁₋₄-alkyl)-amino-C₁₋₃-alkyl, C₁₋₄-alkylcarbonylamino,        C₁₋₄-alkylcarbonylamino-C₁₋₃-alkyl, aminocarbonyl,        C₁₋₄-alkyl-aminocarbonyl, di-(C₁₋₄-alkyl)-aminocarbonyl, cyano,        aminosulphonyl, C₁₋₄-alkyl-aminosulphonyl,        di-(C₁₋₄-alkyl)-aminosulphonyl, C₁₋₄-alkyl-thio,        C₁₋₄-alkyl-sulphinyl, or C₁₋₄-alkyl-sulphonyl and the        substituents may be identical or different,    -   a heterocycle selected from a 4- to 10-membered azacycloalkyl        group, a 6- to 10-membered oxaza-, thiaza-, S,S-dioxothiaza- and        diazacycloalkyl group and a 6- to 10-membered azabicycloalkyl        group,    -   a 1-alkyl-4-piperidinylcarbonyl or 4-alkyl-1-piperazinylcarbonyl        group,        -   while the above-mentioned mono- and bicyclic heterocycles            are bound to Y¹ in formula (II) via a nitrogen or a carbon            atom,        -   in the above-mentioned mono- and bicyclic heterocycles a            methyne group not directly linked to a nitrogen, oxygen or            sulphur atom may be substituted by a fluorine atom and a            methylene group not directly linked to a nitrogen, oxygen or            sulphur atom may be substituted by one or two fluorine            atoms,        -   the above-mentioned mono- and bicyclic heterocycles and the            1-(C₁₋₆-alkyl)-4-piperidinylcarbonyl and            4-(C₁₋₆-alkyl)-1-piperazinylcarbonyl group in the ring may            be mono- to tetrasubstituted by hydroxy, C₁₋₆-alkyl or            hydroxy-C₁₋₃-alkyl groups, or, optionally additionally,            monosubstituted by a cyclo-C₃₋₇-alkyl,            hydroxy-C₃₋₇-cycloalkyl, cyclo-C₃₋₇-alkenyl,            cyclo-C₃₋₇-alkyl-C₁₋₃-alkyl, phenyl-C₁₋₃-alkyl,            pyridyl-C₁₋₃-alkyl, C₁₋₆-alkylcarbonyl,            C₁₋₆-alkylcarbonyl-C₁₋₃-alkyl, hydroxy, C₁₋₆-alkoxy, amino,            C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)amino, phenylcarbonyl,            pyridinylcarbonyl, C₁₋₆-alkoxycarbonyl,            hydroxycarbonyl-carbonyl, C₁₋₆-alkoxycarbonyl-carbonyl,            hydroxycarbonyl-C₁₋₃-alkyl, C₁₋₆-alkoxycarbonyl-C₁₋₃-alkyl,            hydroxycarbonyl-C₁₋₃-alkylcarbonyl,            C₁₋₆-alkoxycarbonyl-C₁₋₃-alkylcarbonyl, aminocarbonyl,            C₁₋₄-alkylaminocarbonyl, di-(C₁₋₄-alkyl)aminocarbonyl,            aminosulphonyl, C₁₋₄-alkylaminosulphonyl,            di-(C₁₋₄-alkyl)aminosulphonyl, C₁₋₃-alkylsulphonyl,            cyclo-C₃₋₇-alkylsulphonyl, aminocarbonyl-C₁₋₃-alkyl,            C₁₋₄-alkylaminocarbonyl-C₁₋₃-alkyl,            di-(C₁₋₄-alkyl)aminocarbonyl-C₁₋₃-alkyl,            hydroxyaminocarbonyl-C₁₋₃-alkyl,            C₁₋₃-alkoxyaminocarbonyl-C₁₋₃-alkyl or            hydroxy-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl group, by a            cyclo-C₃₋₇-alkyl-carbonyl, azacyclo-C₄₋₇-alkyl-carbonyl,            diazacyclo-C₅₋₇-alkyl-carbonyl or            oxazacyclo-C₅₋₇-alkyl-carbonyl group optionally            C₁₋₃-alkyl-substituted in the ring, while the substituents            may be identical or different and may be bound to a cyclic            carbon or cyclic nitrogen atom,            -   while the phenyl and pyridinyl groups contained in the                groups defined above for R⁴ may in turn be mono-, di- or                trisubstituted by halogen atoms, by C₁₋₃-alkyl,                C₂₋₃-alkenyl, C₂₋₃-alkynyl, C₁₋₃-alkoxy, hydroxy, amino,                C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)-amino,                amino-C₁₋₃-alkyl, C₁₋₄-alkyl-amino-C₁₋₃-alkyl,                di-(C₁₋₄-alkyl)-amino-C₁₋₃-alkyl,                C₁₋₄-alkylcarbonylamino,                C₁₋₄-alkylcarbonylamino-C₁₋₃-alkyl, aminocarbonyl,                C₁₋₃-alkyl-aminocarbonyl, di-C₁₋₄-alkyl-aminocarbonyl,                cyano, aminosulphonyl, C₁₋₄-alkyl-aminosulphonyl,                di-(C₁₋₄-alkyl)-aminosulphonyl, C₁₋₃-alkyl-thio,                C₁₋₃-alkyl-sulphinyl, or C₁₋₃-alkyl-sulphonyl, while the                substituents may be identical or different,    -   or also, if Y¹ denotes the carbon atom, the hydroxycarbonyl,        aminomethyl, C₁₋₄-alkyl-aminomethyl or        di-(C₁₋₄-alkyl)-aminomethyl group,    -   R⁵ denotes a hydrogen atom or a hydroxy group,    -   a C₁₋₄-alkyl group, while an unbranched alkyl group may be        substituted in the ω-position by a phenyl, pyridinyl, diazinyl,        amino, C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)-amino,        4-C₁₋₄-alkyl-1-piperazinyl or 4-morpholinyl group,    -   a C₁₋₆-alkoxycarbonyl, cyano or aminocarbonyl group or also, if        Y¹ denotes a nitrogen atom, a pair of free electrons,    -   or, if Y¹ denotes the carbon atom, it may also denote the        fluorine atom, or    -   R⁴ together with R⁵ and Y¹ denote a 4- to 7-membered        cycloaliphatic ring wherein a methylene group may be replaced by        a group —NH—, —N(C₁₋₄-alkyl)-, —N(C₃₋₄-alkenyl)-,        —N(C₃₋₄-alkynyl)-, —N(cyclo-C₃₋₇-alkyl)-,        —N(C₃₋₇-cycloalkyl-C₁₋₃-alkyl)-, —N(hydroxycarbonyl-C₁₋₃-alkyl)-        or —N(C₁₋₆-alkoxycarbonyl-C₁₋₃-alkyl)-,        -   while a hydrogen atom bound to a nitrogen atom in one of the            groups defined for R⁴ hereinbefore may be replaced by a            protecting group,    -   R⁶ and R⁷ which may be identical or different, in each case        denote a hydrogen atom, a C₁₋₄-alkyl group or also, if Y¹        denotes a carbon atom, the fluorine atom, an amino,        C₁₋₄-alkylamino or di-(C₁₋₄-alkyl)-amino group, while the two        C₁₋₄-alkyl groups may be joined together, forming a ring and    -   R⁸ and R⁹, which may be identical or different, in each case        denote a hydrogen atom or a C₁₋₃-alkyl group,

while, unless otherwise stated, all the alkyl, alkenyl and alkynylgroups mentioned or contained in the groups defined hereinbefore may bestraight-chain or branched, every methyne group contained in the groupsdefined hereinbefore may be substituted by a fluorine atom, everymethylene group may be substituted by up to 2 fluorine atoms and everymethyl group may be substituted by up to 3 fluorine atoms and two alkyland alkenyl groups bound to a nitrogen atom may be joined togetherforming a 4- to 7-membered, saturated or unsaturated heterocyclic ring,

all the aromatic and heteroaromatic groups mentioned or contained in thegroups defined hereinbefore may additionally be mono-, di- ortrisubstituted by halogen, by cyano or hydroxy groups and thesubstituents may be identical or different and

by the protecting groups mentioned in the definitions above andhereinafter are meant the protective groups familiar from peptidechemistry, particularly

a phenylalkoxycarbonyl group with 1 to 3 carbon atoms in the alkoxymoiety, optionally substituted in the phenyl nucleus by a halogen atom,by a nitro or phenyl group or by one or two methoxy groups,

-   -   for example the benzyloxycarbonyl, 2-nitro-benzyloxycarbonyl,        4-nitrobenzyloxy-carbonyl, 4-methoxy-benzyloxycarbonyl,        2-chloro-benzyloxycarbonyl, 3-chloro-benzyloxycarbonyl,        4-chloro-benzyloxycarbonyl,        4-biphenylyl-α,α-dimethyl-benzyl-oxycarbonyl or        3,5-dimethoxy-α,α-dimethyl-benzyloxycarbonyl group,

an alkoxycarbonyl group with a total of 1 to 5 carbon atoms in the alkylmoiety,

-   -   for example the methoxycarbonyl, ethoxycarbonyl,        n-propoxycarbonyl, isopropoxy-carbonyl, n-butoxycarbonyl,        1-methyl propoxycarbonyl, 2-methyl propoxy-carbonyl or        tert.butyloxycarbonyl group,

the allyloxycarbonyl, 2,2,2-trichloro-(1,1-dimethylethoxy)carbonyl or9-fluorenylmethoxy-carbonyl group or

the formyl, acetyl or trifluoracetyl group.

In the definitions above and hereinafter a group substituted in thei-position denotes a terminally substituted group,

a halogen atom denotes a fluorine, chlorine, bromine or iodine atom and

a double or triple bond isolated from a heteroatom denotes a double ortriple bond which is linked to a heteroatom via at least one saturatedcarbon atom.

A second embodiment of the present invention comprises the compounds ofthe above general formula (I), wherein

A, X, D, E, G, M, Q and R¹ are defined as mentioned above under thefirst embodiment and

R² denotes the hydrogen atom,

a phenylmethyl group or a C₂₋₇-alkyl group which may be substituted inthe ω-position by a cyclo-C₃₋₇-alkyl, cyclo-C₃₋₇-alkenyl, phenyl,pyridinyl, diazinyl, hydroxy, amino, C₁₋₆-alkylamino,di-(C₁₋₆-alkyl)-amino, C₃₋₆-alkenylamino, di-(C₃₋₆-alkenyl)amino,C₃₋₆-alkynylamino, di-(C₃₋₆-alkynyl)amino, hydroxycarbonyl,C₁₋₆-alkoxycarbonyl, aminocarbonyl, aminocarbonylamino,C₁₋₆-alkylcarbonylamino, C₂₋₆-alkenylcarbonylamino,C₂₋₆-alkynylcarbonylamino, 4-morpholinyl, [bis-(2-hydroxyethyl)]amino,4-(C₁₋₆-alkyl)-1-piperazinyl or 4-(ω-hydroxy-C₂₋₇-alkyl)-1-piperazinylgroup,

a phenyl or pyridinyl group,

-   -   while the phenyl, pyridinyl and diazinyl groups mentioned in the        groups defined R² hereinbefore or contained as substituents        therein may additionally be mono-, di- or trisubstituted in the        carbon skeleton by halogen, by C₁₋₃-alkyl, C₂₋₃-alkenyl,        C₂₋₃-alkynyl, C₁₋₃-alkoxy, hydroxy, amino, C₁₋₃-alkylamino,        di-(C₁₋₃-alkyl)-amino, amino-C₁₋₃-alkyl,        C₁₋₃-alkyl-amino-C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl,        C₁₋₃-alkylcarbonylamino, C₁₋₃-alkylcarbonylamino-C₁₋₃-alkyl,        aminocarbonyl, C₁₋₃-alkyl-aminocarbonyl,        di-(C₁₋₃-alkyl)-aminocarbonyl, cyano, aminosulphonyl,        C₁₋₃-alkyl-aminosulphonyl, di-(C₁₋₃-alkyl)-aminosulphonyl,        C₁₋₃-alkyl-thio, C₁₋₃-alkyl-sulphinyl or C₁₋₃-alkyl-sulphonyl        and the substituents may be identical or different,

R³ denotes the hydrogen atom or a C₁₋₃-alkyl group substituted by aphenyl or pyridinyl group,

-   -   while the C₁₋₃-alkyl group may be linked to an alkyl group        contained in R² or a phenyl or pyridyl contained in R² including        the nitrogen atom to which R² and R³ are bound, forming a 4- to        7-membered ring,

or

R² and R³ together with the enclosed nitrogen atom denote a group ofgeneral formula

wherein

-   -   Y¹ denotes the carbon atom or, if R⁵ denotes a pair of free        electrons, may also denote the nitrogen atom,    -   q and r, if Y¹ denotes the carbon atom, denote the numbers 0, 1        or 2, or    -   q and r, if Y¹ denotes the nitrogen atom, denote the numbers 1        or 2,    -   R⁴ denotes the hydrogen atom, an amino, C₁₋₄-alkyl-amino,        di-(C₁₋₄-alkyl)-alkylamino, C₁₋₆-alkyl, a cyclo-C₃₋₇-alkyl,        cyclo-C₃₋₇-alkenyl, amino-C₂₋₇-alkyl,        C₁₋₄-alkyl-amino-C₂₋₇-alkyl, di-(C₁₋₄-alkyl-amino)-C₂₋₇-alkyl,        aminoiminomethyl, aminocarbonylamino,        C₁₋₄-alkyl-aminocarbonylamino,        di-(C₁₋₄-alkyl)-aminocarbonylamino,        C₁₋₄-alkyl-aminocarbonyl-C₁₋₄-alkyl-amino,        di-(C₁₋₄-alkyl)-aminocarbonyl-C₁₋₄-alkyl-amino,        phenylaminocarbonylamino, aminocarbonyl,        C₁₋₄-alkyl-aminocarbonyl, di-(C₁₋₄-alkyl)-aminocarbonyl,        aminocarbonyl-C₁₋₃-alkyl, C₁₋₄-alkyl-aminocarbonyl-C₁₋₃-alkyl,        di-(C₁₋₄-alkyl)-aminocarbonyl-C₁₋₃-alkyl,        aminocarbonylamino-C₁₋₃-alkyl, C₁₋₆-alkoxycarbonyl,        C₃₋₆-alkenoxycarbonyl, C₃₋₆-alkynoxycarbonyl,        C₁₋₆-alkoxycarbonyl-C₁₋₃-alkyl,        C₁₋₆-alkenoxycarbonyl-C₁₋₃-alkyl,        C₁₋₆-alkynoxycarbonyl-C₁₋₃-alkyl or hydroxycarbonyl-C₁₋₃-alkyl        group,    -   a phenyl, pyridinyl, diazinyl, 1-naphthyl, 2-naphthyl,        pyridinylcarbonyl or phenylcarbonyl group which may be mono-,        di- or trisubstituted in each case in the carbon skeleton by        halogen, by C₁₋₃-alkyl, C₂₋₃-alkenyl, C₂₋₃-alkynyl, C₁₋₃-alkoxy,        hydroxy, amino, C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)-amino,        amino-C₁₋₃-alkyl, C₁₋₄-alkyl-amino-C₁₋₃-alkyl,        di-(C₁₋₄-alkyl)-amino-C₁₋₃-alkyl, C₁₋₄-alkylcarbonylamino,        C₁₋₄-alkylcarbonylamino-C₁₋₃-alkyl, aminocarbonyl,        C₁₋₄-alkyl-aminocarbonyl, di-(C₁₋₄-alkyl)-aminocarbonyl, cyano,        aminosulphonyl, C₁₋₄-alkyl-aminosulphonyl,        di-(C₁₋₄-alkyl)-aminosulphonyl, C₁₋₄-alkyl-thio,        C₁₋₄-alkyl-sulphinyl or C₁₋₄-alkyl-sulphonyl and the        substituents may be identical or different,    -   a heterocycle selected from a 4- to 10-membered azacycloalkyl        group, a 6- to 10-membered oxaza-, thiaza- and diazacycloalkyl        group as well as a 6- to 10-membered azabicycloalkyl group,    -   a 1-alkyl-4-piperidinylcarbonyl or 4-alkyl-1-piperazinylcarbonyl        group,        -   while the above-mentioned mono- and bicyclic heterocycles            are bound to Y¹ in formula (II) via a nitrogen or carbon            atom,        -   in the above-mentioned mono- and bicyclic heterocycles a            methyne group not directly attached to a nitrogen, oxygen or            sulphur atom may be substituted by a fluorine atom and a            methylene group not directly attached to a nitrogen, oxygen            or sulphur atom may be substituted by one or two fluorine            atoms,        -   the above-mentioned mono- and bicyclic heterocycles as well            as the 1-(C₁₋₆-alkyl)-4-piperidinylcarbonyl and            4-(C₁₋₆-alkyl)-1-piperazinylcarbonyl group may be mono- to            tetrasubstituted in the ring by C₁₋₆-alkyl groups, or,            optionally additionally, monosubstituted by a            cyclo-C₃₋₇-alkyl, cyclo-C₃₋₇-alkenyl,            cyclo-C₃₋₇-alkyl-C₁₋₃-alkyl, phenyl-C₁₋₃-alkyl,            pyridyl-C₁₋₃-alkyl, C₁₋₆-alkylcarbonyl, hydroxy,            C₁₋₆-alkoxy, amino, C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)amino,            phenylcarbonyl, pyridinylcarbonyl, hydroxycarbonyl,            hydroxycarbonyl-C₁₋₃-alkyl, C₁₋₆-alkoxycarbonyl,            C₁₋₆-alkoxycarbonyl-C₁₋₃-alkyl, aminocarbonyl,            C₁₋₄-alkylaminocarbonyl, di-(C₁₋₄-alkyl)aminocarbonyl,            C₁₋₃-alkylsulphonyl group, by a cyclo-C₃₋₇-alkylcarbonyl,            azacyclo-C₄₋₇-alkylcarbonyl, diazacyclo-C₅₋₇-alkylcarbonyl            or oxazacyclo-C₅₋₇-alkylcarbonyl group optionally            C₁₋₃-alkylsubstituted in the ring, while the substituents            may be identical or different and may be bound to a cyclic            carbon or cyclic nitrogen atom,            -   while the phenyl and pyridinyl groups contained in the                groups given as definitions for R⁴ hereinbefore may in                turn be mono-, di- or trisubstituted by halogen atoms,                by C₁₋₃-alkyl, C₂₋₃-alkenyl, C₂₋₃-alkynyl, C₁₋₃-alkoxy,                hydroxy, amino, C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)-amino,                amino-C₁₋₃-alkyl, C₁₋₄-alkyl-amino-C₁₋₃-alkyl,                di-(C₁₋₄-alkyl)-amino-C₁₋₃-alkyl,                C₁₋₄-alkylcarbonylamino,                C₁₋₄-alkylcarbonylamino-C₁₋₃-alkyl, aminocarbonyl,                C₁₋₃-alkyl-aminocarbonyl, di-C₁₋₄-alkyl-aminocarbonyl,                cyano, aminosulphonyl, C₁₋₄-alkyl-aminosulphonyl,                di-(C₁₋₄-alkyl)-aminosulphonyl, C₁₋₃-alkylthio,                C₁₋₃-alkyl-sulphinyl or C₁₋₃-alkyl-sulphonyl, while the                substituents may be identical or different,    -   or also, if Y¹ denotes the carbon atom, the hydroxycarbonyl,        aminomethyl, C₁₋₄-alkyl-aminomethyl or        di-(C₁₋₄-alkyl)-aminomethyl group,    -   R⁵ denotes a hydrogen atom,    -   a C₁₋₄-alkyl group, while an unbranched alkyl group may be        substituted in the ω-position by a phenyl, pyridinyl, diazinyl,        amino, C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)-amino,        4-C₁₋₄-alkyl-1-piperazinyl or 4-morpholinyl group,    -   a C₁₋₆-alkoxycarbonyl, cyano or aminocarbonyl group or, if Y¹        denotes a nitrogen atom, a pair of free electrons,    -   or, if Y¹ denotes the carbon atom, also the fluorine atom, or    -   R⁴ together with R⁵ and Y¹ denotes a 4- to 7-membered        cycloaliphatic ring wherein a methylene group may be replaced by        an —NH—, —N(C₁₋₄-alkyl)-, —N(C₃₋₄-alkenyl)-, —N(C₃₋₄-alkynyl)-,        —N(cyclo-C₃₋₇-alkyl)- or —N(C₃₋₇-cycloalkyl-C₁₋₃-alkyl)- group,        -   while a hydrogen atom bound to a nitrogen atom in one of the            groups defined for R⁴ hereinbefore may be replaced by a            protecting group,    -   R⁶ and R⁷ which may be identical or different, in each case        denote a hydrogen atom, a C₁₋₄-alkyl group or, if Y¹ denotes a        carbon atom, the fluorine atom, a C₁₋₄-alkylamino or        di-(C₁₋₄-alkyl)-amino group, while the two C₁₋₄-alkyl groups may        be joined together, forming a ring, and    -   R⁸ and R⁹, which may be identical or different, in each case        denote a hydrogen atom or a C₁₋₃-alkyl group,

while, unless otherwise stated, all the alkyl, alkenyl and alkynylgroups mentioned or contained in the groups defined hereinbefore may bestraight-chain or branched, each methyne group contained in the groupsdefined hereinbefore may be substituted by a fluorine atom, eachmethylene group may be substituted by up to 2 fluorine atoms and eachmethyl group may be substituted by up to 3 fluorine atoms and two alkyland alkenyl groups bound to a nitrogen atom may be joined together,forming a 4- to 7-membered, saturated or unsaturated heterocyclic ring,

all the aromatic and heteroaromatic groups mentioned or contained in thegroups defined hereinbefore may additionally be mono-, di- ortrisubstituted by halogen, by cyano or hydroxy groups and thesubstituents may be identical or different,

the tautomers, the isomers, the diastereomers, the enantiomers, thehydrates, the mixtures thereof and the salts thereof as well as thehydrates of the salts, particularly the physiologically acceptable saltsthereof with inorganic or organic acids or bases.

A third embodiment of the present invention consists of the compounds ofthe above general formula (I), wherein

A, X, D, E, G, M, Q, R² and R³ are as defined hereinbefore under thefirst or second embodiment and

R¹ denotes a mono- or diunsaturated 5- to 7-membered aza, diaza, triazaor thiaza heterocycle,

-   -   while the above-mentioned heterocycles are linked via a carbon        or nitrogen atom or    -   are linked spirocyclically via a carbon and a nitrogen atom, via        a carbon and an oxygen atom or via a carbon and a sulphur atom,    -   contain one or two carbonyl groups adjacent to a nitrogen atom,    -   may be substituted at a carbon atom by a phenyl, pyridinyl,        diazinyl, thienyl, pyrrolyl, 1,3-thiazolyl, isoxazolyl,        pyrazolyl or 1-(C₁₋₄-alkyl)-pyrazolyl group and    -   an olefinic double bond of one of the above-mentioned        unsaturated heterocycles may be fused to a phenyl, naphthyl,        pyridine, diazine, thienyl or quinoline ring or to a        1H-quinolin-2-one ring optionally substituted at the nitrogen        atom by a methyl group,        -   while the phenyl, pyridinyl, diazinyl, thienyl, pyrrolyl,            1,3-thiazolyl, isoxazolyl, pyrazolyl or            1-(C₁₋₄-alkyl)-pyrazolyl groups contained in R¹ and the            benzo-, pyrido- and diazino-fused heterocycles in the carbon            skeleton may additionally be mono-, di- or trisubstituted by            halogen, by C₁₋₆-alkyl, cyclo-C₃₋₇-alkyl,            cyclo-C₃₋₇-alkenyl, C₁₋₆-alkoxy, hydroxycarbonyl,            C₁₋₆-alkoxycarbonyl, cyano, hydroxy, amino, C₁₋₄-alkylamino,            di-C₁₋₄-alkylamino, C₁₋₄-alkylcarbonylamino or            C₁₋₄-alkylcarbonyl groups, while the substituents may be            identical or different,

and, unless otherwise stated, all the alkyl, alkenyl and alkynyl groupsmentioned or contained in the groups defined hereinbefore under R¹ maybe straight-chain or branched, every methyne group contained in thegroups defined hereinbefore may be substituted by a fluorine atom, everymethylene group may be substituted by up to 2 fluorine atoms and everymethyl group may be substituted by up to 3 fluorine atoms and two alkyland alkenyl groups bound to a nitrogen atom may be joined togetherforming a 4- to 7-membered, saturated or unsaturated heterocyclic ring,and

all the aromatic and heteroaromatic groups mentioned or contained in thegroups defined hereinbefore under R¹ may additionally be mono-, di- ortrisubstituted by halogen, by cyano or hydroxy groups and thesubstituents may be identical or different,

the tautomers, the isomers, the diastereomers, the enantiomers, thehydrates thereof, the mixtures thereof and the salts thereof and thehydrates of the salts, particularly the physiologically acceptable saltsthereof with inorganic or organic acids or bases.

A fourth embodiment of the present invention consists of the compoundsof the above general formula (I), wherein

A, X, D, E, G, M, Q, R² and R³ are defined as mentioned previously underthe first or second embodiment and

R¹ denotes a monounsaturated 5- to 7-membered diaza or triazaheterocycle,

-   -   while the above-mentioned heterocycles are linked via a nitrogen        atom or    -   are linked spirocyclically via a carbon and a nitrogen atom or        via a carbon and an oxygen atom,    -   contain a carbonyl group adjacent to a nitrogen atom,    -   may additionally be substituted by a phenyl group at a carbon        atom and    -   an olefinic double bond of one of the above-mentioned        unsaturated heterocycles may be fused to a phenyl, thienyl or        quinoline ring,        -   while the phenyl groups and benzo-fused heterocycles in the            carbon skeleton contained in R¹ may additionally be mono-,            di- or trisubstituted by halogen, by methyl, methoxy,            difluoromethyl, trifluoromethyl, hydroxy, amino,            C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)-amino, acetylamino, acetyl,            hydroxycarbonyl, C₁₋₃-alkoxycarbonyl, cyano, difluoromethoxy            or trifluoromethoxy groups, while the substituents may be            identical or different, but are preferably unsubstituted or            monosubstituted by a halogen atom or by a methyl or methoxy            group,

while, unless otherwise stated, all the alkyl groups mentioned orcontained in the groups defined hereinbefore under R¹ may bestraight-chain or branched, every methyne group contained in the groupsdefined hereinbefore may be substituted by a fluorine atom, everymethylene group may be substituted by up to 2 fluorine atoms and everymethyl group may be substituted by up to 3 fluorine atoms,

the tautomers, the isomers, the diastereomers, the enantiomers, thehydrates thereof, the mixtures thereof and the salts thereof and thehydrates of the salts, particularly the physiologically acceptable saltsthereof with inorganic or organic acids or bases.

A fifth embodiment of the present invention consists of the compounds ofthe above general formula (I), wherein

A, X, D, E, G, M, Q, R² and R³ are defined as mentioned hereinbeforeunder the first or second embodiment and

R¹ denotes a 1,3,4,5-tetrahydro-1,3-benzodiazepin-2-on-3-yl,3,4-dihydro-1H-quinazolin-2-on-3-yl,5-phenyl-2,4-dihydro-1,2,4-triazol-3-on-2-yl,1,3-dihydro-imidazo[4,5-c]quinolin-2-on-3-yl,1,3-dihydro-naphth[1,2-d]imidazol-2-on-3-yl,1,3-dihydro-benz-imidazol-2-on-3-yl,4-phenyl-1,3-dihydro-imidazol-2-on-1-yl,3,4-dihydro-1H-thieno-[3,2-d]pyrimidin-2-on-3-yl or3,4-dihydro-1H-thieno[3,4-d]pyrimidin-2-on-3-yl group,

-   -   while the heterocycles in the carbon skeleton mentioned under R¹        hereinbefore may additionally be monosubstituted by a methoxy        group,

all the aromatic and heteroaromatic groups mentioned or contained in thegroups defined hereinbefore under R¹ may additionally be mono-, di- ortrisubstituted by halogen atoms, by cyano or hydroxy groups and thesubstituents may be identical or different,

the tautomers, the isomers, the diastereomers, the enantiomers, thehydrates thereof, the mixtures thereof and the salts thereof and thehydrates of the salts, particularly the physiologically acceptable saltsthereof with inorganic or organic acids or bases.

A sixth embodiment of the present invention consists of the compounds ofthe above general formula (I), wherein

A, X, R¹, R² and R³ are defined as mentioned hereinbefore under thefirst, second, third, fourth or fifth embodiment and

(a) D, E independently of one another in each case denote a methynegroup or the nitrogen atom and

-   -   G denotes a methyne group substituted by the group R^(a),    -   M denotes a methyne group substituted by the group R^(b),    -   Q denotes a methyne group substituted by the group R^(c),        -   while one or two of the groups G, M and Q in each case may            also represent a nitrogen atom,

or

(b) D and E in each case denote a methyne group, while one of the groupsD and E may also represent a nitrogen atom, and

-   -   G, M and Q in each case denote a nitrogen atom,

while R^(a), R^(b) and R^(c) independently of one another in each casedenote a hydrogen or halogen atom, a C₁₋₄-alkyl, C₂₋₄-alkenyl,C₂₋₄-alkynyl, cyclo-C₃₋₆-alkyl, cyclo-C₃₋₆-alkenyl, cyano, hydroxy,hydroxy-C₁₋₄-alkyl, hydroxy-C₃₋₄-alkenyl, hydroxy-C₃₋₄-alkynyl,C₁₋₄-alkoxy, C₁₋₄-alkoxy-C₁₋₄-alkyl, C₁₋₄-alkoxy-C₃₋₄-alkenyl,C₁₋₄-alkoxy-C₃₋₄-alkynyl, thiohydroxy, C₁₋₄-alkylthio, amino,C₁₋₄-alkyl-amino, C₃₋₄-alkenyl-amino, C₃₋₄-alkynyl-amino,di-(C₁₋₄-alkyl)-amino, di-(C₃₋₄-alkenyl)-amino, di-(C₃₋₄-alkynyl)-amino,amino-C₁₋₄-alkyl, C₁₋₃-alkyl-amino-C₁₋₄-alkyl,di-(C₁₋₃-alkyl)-amino-C₁₋₄-alkyl, amino-C₃₋₄-alkenyl,C₁₋₃-alkyl-amino-C₃₋₄-alkenyl, di-(C₁₋₃-alkyl)-amino-C₃₋₄-alkenyl,amino-C₃₋₄-alkynyl, C₁₋₃-alkyl-amino-C₃₋₄-alkynyl,di-(C₁₋₃-alkyl)-amino-C₃₋₄-alkynyl, hydroxycarbonyl, phenylcarbonyl,pyridylcarbonyl, C₁₋₄-alkyl-carbonyl, formyl, C₁₋₄-alkoxy-carbonyl,C₃₋₄-alkenoxy-carbonyl, C₃₋₄-alkynoxy-carbonyl, aminocarbonyl,C₁₋₄-alkyl-aminocarbonyl, C₃₋₄-alkenyl-aminocarbonyl,C₃₋₄-alkynyl-aminocarbonyl, di-(C₁₋₄-alkyl)-aminocarbonyl,di-(C₃₋₄-alkenyl)-aminocarbonyl, di-C₃₋₄-(alkynyl)-aminocarbonyl,formylamino, C₁₋₄-alkyl-carbonylamino, formyl-C₁₋₄-alkyl-amino,formyl-C₃₋₄-alkenyl-amino, formyl-C₃₋₄-alkynyl-amino,C₁₋₄-alkyl-carbonyl-C₁₋₄-alkyl-amino,C₁₋₄-alkyl-carbonyl-C₃₋₄-alkenyl-amino,C₁₋₄-alkyl-carbonyl-C₃₋₄-alkynyl-amino, C₁₋₄-alkyl-sulphonyl,C₂₋₄-alkenyl-sulphonyl, C₂₋₄-alkynyl-sulphonyl, C₁₋₄-alkyl-sulphinyl,C₂₋₄-alkenyl-sulphinyl, C₂₋₄-alkynyl-sulphinyl,C₁₋₄-alkyl-sulphonylamino, C₁₋₄-alkyl-sulphonyl-C₁₋₄-alkylamino,C₁₋₄-alkyl-sulphonyl-C₃₋₄-alkenylamino,C₁₋₄-alkyl-sulphonyl-C₃₋₄-alkynylamino, aminosulphonyl,C₁₋₄-alkylaminosulphonyl, di-(C₁₋₄-alkyl)-aminosulphonyl,C₃₋₄-alkenylaminosulphonyl, di-(C₃₋₄-alkenyl)-aminosulphonyl,C₃₋₄-alkynylaminosulphonyl or di-(C₃₋₄-alkynyl)-aminosulphonyl group,

-   -   with the provisos that, if none of the groups D, E, G, M and Q        denotes a nitrogen atom,    -   (i) R^(a) does not denote a hydrogen atom, if R^(b) and R^(c) in        each case denote a C₁₋₄-alkyl group,    -   (ii) R^(c) does not denote a hydrogen atom, if R^(a) and R^(b)        in each case denote a C₁₋₄-alkyl group,    -   (iii) R^(a) does not take on the meanings of a hydrogen,        fluorine, chlorine, bromine or iodine atom or a difluoro- or        trifluoromethyl group, if R^(c) denotes a C₁₋₄-alkyl,        C₂₋₄-alkenyl or C₂₋₄-alkynyl group and R^(b) denotes a chlorine        or bromine atom or an amino, methylamino or hydroxy group,    -   (iv) R^(c) does not take on the meanings of a hydrogen,        fluorine, chlorine, bromine or iodine atom or a difluoro- or        trifluoromethyl group, if R^(a) denotes a C₁₋₄-alkyl,        C₂₋₄-alkenyl or C₂₋₄-alkynyl group and R^(b) denotes a chlorine        or bromine atom, an amino, methylamino or hydroxy group,

while, unless otherwise stated, all the alkyl, alkenyl and alkynylgroups mentioned or contained in the groups defined hereinbefore forR^(a), R^(b) and R^(c) may be straight-chain or branched, every methynegroup contained in the groups defined hereinbefore may be substituted bya fluorine atom, every methylene group may be substituted by up to 2fluorine atoms and every methyl group may be substituted by up to 3fluorine atoms and two alkyl and alkenyl groups bound to a nitrogen atommay be joined together forming a 4- to 7-membered, saturated orunsaturated heterocyclic ring,

the double and triple bonds of the C₃₋₄-alkenyl or C₃₋₄-alkynyl groupscontained in the groups given as definitions for R^(a), R^(b) and R^(c)hereinbefore may be isolated from any heteroatoms optionally alsocontained in these groups,

and all the aromatic and heteroaromatic groups mentioned or contained inthe groups defined hereinbefore may additionally be mono-, di- ortrisubstituted by halogen, by cyano or hydroxy groups and thesubstituents may be identical or different,

the tautomers, the isomers, the diastereomers, the enantiomers, thehydrates thereof, the mixtures thereof and the salts thereof and thehydrates of the salts, particularly the physiologically acceptable saltsthereof with inorganic or organic acids or bases.

A seventh embodiment of the present invention consists of the compoundsof the above general formula (I), wherein

A, X, R¹, R² and R³ are defined as mentioned hereinbefore under thefirst, second, third, fourth or fifth embodiment and

(a) D, E independently of one another in each case denote a methynegroup or the nitrogen atom and

-   -   G denotes a methyne group substituted by the group R^(a),    -   M denotes a methyne group substituted by the group R^(b),    -   Q denotes a methyne group substituted by the group R^(c),        -   while one or two of the groups G, M and Q in each case may            also represent a nitrogen atom,

or

(b) D and E in each case denote a methyne group, while one of the groupsD and E may also represent a nitrogen atom, and

-   -   G, M and Q in each case denote a nitrogen atom,

while R^(a), R^(b) and R^(c) independently of one another in each casedenote a hydrogen or halogen atom, a C₁₋₄-alkyl, C₂₋₄-alkenyl,C₂₋₄-alkynyl, cyclo-C₃₋₆-alkyl, cyclo-C₃₋₆-alkenyl, cyano, hydroxy,hydroxy-C₁₋₂-alkyl, hydroxy-C₃-alkenyl, hydroxy-C₃-alkynyl, C₁₋₄-alkoxy,C₁₋₄-alkoxy-C₁₋₂-alkyl, amino, C₁₋₄-alkyl-amino, C₃₋₄-alkenyl-amino,C₃₋₄-alkynyl-amino, di-(C₁₋₄-alkyl)-amino, di-(C₃₋₄-alkenyl)-amino,di-(C₃₋₄-alkynyl)-amino, amino-C₁₋₂-alkyl, C₁₋₃-alkyl-amino-C₁₋₂-alkyl,di-(C₁₋₃-alkyl)-amino-C₁₋₂-alkyl, amino-C₃-alkenyl,C₁₋₃-alkyl-amino-C₃-alkenyl, di-(C₁₋₃-alkyl)-amino-C₃-alkenyl,amino-C₃-alkynyl, C₁₋₃-alkyl-amino-C₃-alkynyl,di-(C₁₋₃-alkyl)-amino-C₃-alkynyl, hydroxycarbonyl, C₁₋₄-alkyl-carbonyl,formyl, C₁₋₄-alkoxy-carbonyl, aminocarbonyl, C₁₋₄-alkyl-aminocarbonyl,di-(C₁₋₄-alkyl)-aminocarbonyl, formylamino, C₁₋₄-alkyl-carbonylamino,formyl-C₁₋₄-alkyl-amino, C₁₋₄-alkyl-carbonyl-C₁₋₄-alkyl-amino,C₁₋₄-alkyl-sulphonyl, C₁₋₄-alkyl-sulphinyl, C₁₋₄-alkyl-sulphonylamino,C₁₋₄-alkyl-sulphonyl-C₁₋₄-alkylamino, aminosulphonyl,C₁₋₄-alkylaminosulphonyl or di-(C₁₋₄-alkyl)-aminosulphonyl group,

-   -   with the provisos that, if none of the groups D, E, G, M and Q        denotes a nitrogen atom,    -   (i) R^(a) does not denote a hydrogen atom if R^(b) and R^(c) in        each case denote a C₁₋₄-alkyl group,    -   (ii) R^(c) does not denote a hydrogen atom if R^(a) and R^(b) in        each case denote a C₁₋₄-alkyl group,    -   (iii) R^(a) does not take on the meanings of a hydrogen,        fluorine, chlorine, bromine or iodine atom or a difluoro- or        trifluoromethyl group if R^(c) denotes a C₁₋₄-alkyl,        C₂₋₄-alkenyl or C₂₋₄-alkynyl group and R^(b) denotes a chlorine        or bromine atom, an amino, methylamino or hydroxy group,    -   (iv) R^(c) does not take on the meanings of a hydrogen,        fluorine, chlorine, bromine or iodine atom or a difluoro- or        trifluoromethyl group if R^(a) denotes a C₁₋₄-alkyl,        C₂₋₄-alkenyl or C₂₋₄-alkynyl group and R^(b) denotes a chlorine        or bromine atom, an amino, methylamino or hydroxy group,

while, unless otherwise stated, all the alkyl, alkenyl and alkynylgroups mentioned or contained in the groups defined hereinbefore forR^(a), R^(b) and R^(c) may be straight-chain or branched, every methynegroup contained in the groups defined hereinbefore may be substituted bya fluorine atom, every methylene group may be substituted by up to 2fluorine atoms and every methyl group may be substituted by up to 3fluorine atoms and two alkyl and alkenyl groups bound to a nitrogen atommay be joined together forming a 4- to 7-membered, saturated orunsaturated heterocyclic ring,

the double and triple bonds of the C₃₋₄-alkenyl or C₃₋₄-alkynyl groupscontained in the groups given as definitions for R^(a), R^(b) and R^(c)hereinbefore may be isolated from any heteroatoms optionally alsocontained in these groups,

the tautomers, the isomers, the diastereomers, the enantiomers, thehydrates thereof, the mixtures thereof and the salts thereof and thehydrates of the salts, particularly the physiologically acceptable saltsthereof with inorganic or organic acids or bases.

An eighth embodiment of the present invention consists of the compoundsof the above general formula (I), wherein

A, X, R¹, R² and R³ are defined as mentioned hereinbefore under thefirst, second, third, fourth or fifth embodiment and

(a) D, E independently of one another in each case denote a methynegroup or the nitrogen atom and

-   -   G denotes a methyne group substituted by the group R^(a),    -   M denotes a methyne group substituted by the group R^(b),    -   Q denotes a methyne group substituted by the group R^(c),        -   while one or two of the groups G, M and Q in each case may            also represent a nitrogen atom,

or

(b) D and E in each case denote a methyne group, while one of the groupsD and E may also represent a nitrogen atom, and

-   -   G, M and Q in each case denote a nitrogen atom,

while R^(a), R^(b) and R^(c) independently of one another in each casedenote a hydrogen or halogen atom, a C₁₋₄-alkyl, C₂₋₄-alkenyl,C₂₋₄-alkynyl, cyclo-C₃₋₆-alkyl, cyclo-C₃₋₆-alkenyl, cyano, hydroxy,hydroxy-C₁₋₂-alkyl, C₁₋₄-alkoxy, amino, C₁₋₄-alkyl-amino,di-(C₁₋₄-alkyl)-amino, amino-C₁₋₂-alkyl, C₁₋₃-alkyl-amino-C₁₋₂-alkyl,di-(C₁₋₃-alkyl)-amino-C₁₋₂-alkyl, hydroxycarbonyl, C₁₋₄-alkyl-carbonyl,formyl, C₁₋₄-alkoxy-carbonyl, aminocarbonyl, C₁₋₄-alkyl-aminocarbonyl,di-(C₁₋₄-alkyl)-aminocarbonyl, formylamino, C₁₋₄-alkyl-carbonylamino,formyl-C₁₋₄-alkyl-amino or C₁₋₄-alkyl-carbonyl-C₁₋₄-alkyl-amino group,

-   -   with the provisos that, if none of the groups D, E, G, M and Q        denotes a nitrogen atom,    -   (i) R^(a) does not denote a hydrogen atom if R^(b) and R^(c) in        each case denote a C₁₋₄-alkyl group,    -   (ii) R^(c) does not denote a hydrogen atom if R^(a) and R^(b) in        each case denote a C₁₋₄-alkyl group,    -   (iii) R^(a) does not take on the meanings of a hydrogen,        fluorine, chlorine, bromine or iodine atom or a difluoro- or        trifluoromethyl group if R^(c) denotes a C₁₋₄-alkyl,        C₂₋₄-alkenyl or C₂₋₄-alkynyl group and R^(b) denotes a chlorine        or bromine atom, an amino, methylamino or hydroxy group,    -   (iv) R^(c) does not take on the meanings of a hydrogen,        fluorine, chlorine, bromine or iodine atom or a difluoro- or        trifluoromethyl group if R^(a) denotes a C₁₋₄-alkyl,        C₂₋₄-alkenyl or C₂₋₄-alkynyl group and R^(b) denotes a chlorine        or bromine atom, an amino, methylamino or hydroxy group,

while, unless otherwise stated, all the alkyl alkenyl and alkynyl groupsmentioned or contained in the groups defined hereinbefore for R^(a),R^(b) and R^(c) may be straight-chain or branched, every methyne groupcontained in the groups defined hereinbefore may be substituted by afluorine atom, every methylene group may be substituted by up to 2fluorine atoms and every methyl group may be substituted by up to 3fluorine atoms and two alkyl and alkenyl groups bound to a nitrogen atommay be joined together forming a 4- to 7-membered, saturated orunsaturated heterocyclic ring,

the tautomers, the isomers, the diastereomers, the enantiomers, thehydrates thereof, the mixtures thereof and the salts thereof and thehydrates of the salts, particularly the physiologically acceptable saltsthereof with inorganic or organic acids or bases.

A ninth embodiment of the present invention consists of the compounds ofthe above general formula (I), wherein

A, X, R¹, R² and R³ are defined as mentioned hereinbefore under thefirst, second, third, fourth or fifth embodiment and

(a) D, E independently of one another in each case denote a methynegroup or the nitrogen atom and

-   -   G denotes a methyne group substituted by the group R^(a),    -   M denotes a methyne group substituted by the group R^(b),    -   Q denotes a methyne group substituted by the group R^(c),        -   while one or two of the groups G, M and Q in each case may            also represent a nitrogen atom,

or

(b) D and E in each case denote a methyne group, while one of the groupsD and E may also represent a nitrogen atom, and

-   -   G, M and Q in each case denote a nitrogen atom,

while R^(a), R^(b) and R^(c) independently of one another in each casedenote a hydrogen or—halogen atom, a methyl, difluoromethyl,trifluoromethyl, ethyl, vinyl, ethynyl, cyano, hydroxy, methoxy,difluoromethoxy, trifluoromethoxy, amino, methylamino or dimethylaminogroup,

-   -   with the provisos that, if none of the groups D, E, G, M and Q        denotes a nitrogen atom,    -   (i) R^(a) does not denote a hydrogen atom if R^(b) and R^(c) in        each case denote a methyl or ethyl group,    -   (ii) R^(c) does not denote a hydrogen atom if R^(a) and R^(b) in        each case denote a methyl or ethyl group,    -   (iii) R^(a) does not take on the meanings of a hydrogen,        fluorine, chlorine, bromine or iodine atom or a difluoro- or        trifluoromethyl group if R^(c) denotes a methyl, ethyl, vinyl or        ethynyl group and R^(b) denotes a chlorine or bromine atom, an        amino, methylamino or hydroxy group,    -   (iv) R^(c) does not take on the meanings of a hydrogen,        fluorine, chlorine, bromine or iodine atom or a difluoro- or        trifluoromethyl group if R^(a) denotes a methyl, ethyl, vinyl or        ethynyl group and R^(b) denotes a chlorine or bromine atom, an        amino, methylamino or hydroxy group,

the tautomers, the isomers, the diastereomers, the enantiomers, thehydrates thereof, the mixtures thereof and the salts thereof and thehydrates of the salts, particularly the physiologically acceptable saltsthereof with inorganic or organic acids or bases.

A tenth embodiment of the present invention consists of the compounds ofthe above general formula (I), wherein

A, X, D, E, G, M, Q and R¹ are defined as mentioned hereinbefore underthe first, second, third, fourth, fifth, sixth, seventh, eighth or ninthembodiment and

R² denotes the hydrogen atom or

a phenylmethyl group or a C₂₋₇-alkyl group which may be substituted inthe ω-position by a cyclo-C₃₋₇-alkyl, cyclo-C₃₋₇-alkenyl, phenyl,pyridinyl, hydroxy, amino, C₁₋₆-alkylamino, di-(C₁₋₆-alkyl)-amino,hydroxycarbonyl, C₁₋₆-alkoxycarbonyl, aminocarbonyl, aminocarbonylamino,C₁₋₆-alkylamino, 4-morpholinyl group,

-   -   while the phenyl and pyridinyl groups mentioned in the groups        defined for R² hereinbefore or contained as substituents may        additionally be mono-, di- or trisubstituted in the carbon        skeleton by halogen, by C₁₋₃-alkyl, C₁₋₃-alkoxy, hydroxy, amino,        C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, amino-C₁₋₃-alkyl,        C₁₋₃-alkylamino-C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl,        C₁₋₃-alkylcarbonylamino, C₁₋₃-alkylcarbonyl-C₁₋₃-alkylamino,        aminocarbonyl, C₁₋₃-alkylaminocarbonyl or        di-(C₁₋₃-alkyl)-aminocarbonyl groups and the substituents may be        identical or different,

R³ denotes the hydrogen atom or a C₁₋₃-alkyl group or

R² and R³ together with the enclosed nitrogen atom denote a group ofgeneral formula

wherein

-   -   Y¹ denotes the carbon atom or, if R⁵ denotes a pair of free        electrons, it may also    -   denote the nitrogen atom,    -   q and r, if Y¹ denotes the carbon atom, denote the numbers 0 or        1 or    -   q and r, if Y¹ denotes the nitrogen atom, denote the numbers 1        or 2,    -   R⁴ denotes the hydrogen atom, an amino, C₁₋₄-alkyl-amino,        di-(C₁₋₄-alkyl)-alkylamino, C₁₋₆-alkyl, a cyclo-C₃₋₇-alkyl or        cyclo-C₃₋₇-alkenyl group optionally substituted by a        hydroxycarbonyl, C₁₋₆-alkoxycarbonyl, hydroxycarbonyl-C₁₋₃-alkyl        or C₁₋₆-alkoxycarbonyl-C₁₋₃-alkyl group, an amino-C₂₋₇-alkyl,        C₁₋₄-alkyl-amino-C₂₋₇-alkyl, di-(C₁₋₄-alkyl-amino)-C₂₋₇-alkyl,        C₁₋₄-alkyl-aminocarbonyl, di-(C₁₋₄-alkyl)-aminocarbonyl,        aminocarbonyl-C₁₋₃-alkyl, C₁₋₄-alkyl-aminocarbonyl-C₁₋₃-alkyl,        di-(C₁₋₄-alkyl)-aminocarbonyl-C₁₋₃-alkyl,        aminocarbonylamino-C₁₋₃-alkyl, C₁₋₆-alkoxycarbonyl,        C₁₋₆-alkoxycarbonyl-C₁₋₃-alkyl or hydroxycarbonyl-C₁₋₃-alkyl        group,    -   a phenyl, pyridinyl or diazinyl group which may be substituted        in each case by a halogen, a C₁₋₃-alkyl, C₁₋₃-alkoxy, hydroxy,        amino, C₁₋₄-alkyl-amino, di-(C₁₋₄-alkyl)-amino,        amino-C₁₋₃-alkyl, C₁₋₄-alkyl-amino-C₁₋₃-alkyl,        di-(C₁₋₄-alkyl)-amino-C₁₋₃-alkyl group,    -   a heterocycle selected from a 4- to 7-membered azacycloalkyl        group, a 6- to 7-membered oxaza-, S,S-dioxothiaza- and        diazacycloalkyl group and a 7- to 9-membered azabicycloalkyl        group,        -   while the above-mentioned mono- and bicyclic heterocycles            are bound to Y¹ in formula (II) via a nitrogen or a carbon            atom,        -   in the above-mentioned mono- and bicyclic heterocycles a            methylene group not directly linked to a nitrogen, oxygen or            sulphur atom may be substituted by one or two fluorine atoms            and        -   the above-mentioned mono- and bicyclic heterocycles may be            mono- or disubstituted by hydroxy, C₁₋₃-alkyl or            hydroxy-C₁₋₃-alkyl groups or monosubstituted by a benzyl,            cyclo-C₃₋₆-alkyl, hydroxycyclo-C₃₋₆-alkyl,            cyclo-C₃₋₆-alkyl-C₁₋₃-alkyl, C₁₋₄-alkylcarbonyl,            C₁₋₄-alkylcarbonyl-C₁₋₃-alkyl, hydroxy, C₁₋₄-alkoxy, amino,            C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)-amino, C₁₋₃-alkoxycarbonyl,            hydroxycarbonyl-carbonyl, C₁₋₃-alkoxycarbonyl-carbonyl,            hydroxycarbonyl-C₁₋₃-alkyl, C₁₋₃-alkoxycarbonyl-C₁₋₃-alkyl,            hydroxycarbonyl-C₁₋₃-alkylcarbonyl,            C₁₋₃-alkoxycarbonyl-C₁₋₃-alkylcarbonyl, aminosulphonyl,            C₁₋₄-alkylaminosulphonyl, di-(C₁₋₄-alkyl)-aminosulphonyl,            C₁₋₃-alkylsulphonyl, cyclo-C₃₋₇-alkylsulphonyl,            aminocarbonyl-C₁₋₃-alkyl,            C₁₋₄-alkylaminocarbonyl-C₁₋₃-alkyl,            di-(C₁₋₄-alkyl)-aminocarbonyl-C₁₋₃-alkyl,            hydroxyaminocarbonyl-C₁₋₃-alkyl,            C₁₋₃-alkoxyaminocarbonyl-C₁₋₃-alkyl or            hydroxy-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl group,    -   or also, if Y¹ denotes the carbon atom, the hydroxycarbonyl,        aminomethyl, C₁₋₄-alkyl-aminomethyl or        di-(C₁₋₄-alkyl)-aminomethyl group,    -   R⁵ denotes a hydrogen atom, a C₁₋₃-alkyl group or, if Y¹ denotes        a nitrogen atom, also a pair of free electrons,    -   R⁶ and R⁷ which may be identical or different, in each case        denote a hydrogen atom, a C₁₋₃-alkyl group or also, if Y¹        denotes a carbon atom, an amino, C₁₋₃-alkylamino or        di-(C₁₋₃-alkyl)-amino group, while the two C₁₋₃-alkyl groups may        be joined together, forming a ring and    -   R⁸ and R⁹, which may be identical or different, in each case        denote a hydrogen atom or a C₁₋₃-alkyl group,

while, unless otherwise stated, all the alkyl, alkenyl and alkynylgroups mentioned or contained in the groups defined hereinbefore may bestraight-chain or branched, every methyne group contained in the groupsdefined hereinbefore may be substituted by a fluorine atom, everymethylene group may be substituted by up to 2 fluorine atoms and everymethyl group may be substituted by up to 3 fluorine atoms and two alkyland alkenyl groups bound to a nitrogen atom may be joined togetherforming a 4- to 7-membered, saturated or unsaturated heterocyclic ring,

all the aromatic and heteroaromatic groups mentioned or contained in thegroups defined hereinbefore may additionally be mono-, di- ortrisubstituted by halogen, by cyano or hydroxy groups and thesubstituents may be identical or different,

the tautomers, the isomers, the diastereomers, the enantiomers, thehydrates thereof, the mixtures thereof and the salts thereof and thehydrates of the salts, particularly the physiologically acceptable saltsthereof with inorganic or organic acids or bases.

An eleventh embodiment of the present invention comprises the compoundsof the above general formula (I), wherein

A, X, D, E, G, M, Q and R¹ are defined as hereinbefore under the first,second, third, fourth, fifth, sixth, seventh, eighth or ninth embodimentand

R² denotes the hydrogen atom or

a phenylmethyl group or a C₂₋₇-alkyl group which may be substituted inthe ω-position by a cyclo-C₃₋₇-alkyl, cyclo-C₃₋₇-alkenyl, phenyl,pyridinyl, hydroxy, amino, C₁₋₆-alkylamino, di-(C₁₋₆-alkyl)-amino,hydroxycarbonyl, C₁₋₆-alkoxycarbonyl, aminocarbonyl, aminocarbonylamino,C₁₋₆-alkylamino, 4-morpholinyl group,

-   -   while the phenyl and pyridinyl groups mentioned in the groups        given as definitions for R² or contained as substituents therein        may additionally be mono-, di- or trisubstituted in the carbon        skeleton by halogen, by C₁₋₃-alkyl, C₁₋₃-alkoxy, hydroxy, amino,        C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, amino-C₁₋₃-alkyl,        C₁₋₃-alkylamino-C₁₋₃-alkyl, 25 di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl,        C₁₋₃-alkylcarbonylamino, C₁₋₃-alkylcarbonyl-C₁₋₃-alkylamino,        aminocarbonyl, C₁₋₃-alkylaminocarbonyl or        di-(C₁₋₃-alkyl)-aminocarbonyl groups and the substituents may be        identical or different,

R³ denotes the hydrogen atom or a C₁₋₃-alkyl group or

R² and R³ together with the enclosed nitrogen atom denote a group ofgeneral formula

wherein

-   -   Y¹ denotes the carbon atom or, if R⁵ denotes a pair of free        electrons, it may also denote the nitrogen atom,    -   q and r, if Y¹ denotes the carbon atom, denote the numbers 0 or        1 or    -   q and r, if Y¹ denotes the nitrogen atom, denote the numbers 1        or 2,    -   R⁴ denotes the hydrogen atom, an amino, C₁₋₄-alkyl-amino,        di-(C₁₋₄-alkyl)-alkylamino, C₁₋₆-alkyl, cyclo-C₃₋₇-alkyl,        cyclo-C₃₋₇-alkenyl, amino-C₂₋₇-alkyl,        C₁₋₄-alkyl-amino-C₂₋₇-alkyl, di-(C₁₋₄-alkyl-amino)-C₂₋₇-alkyl,        C₁₋₄-alkyl-aminocarbonyl, di-(C₁₋₄-alkyl)-aminocarbonyl,        aminocarbonyl-C₁₋₃-alkyl, C₁₋₄-alkyl-aminocarbonyl-C₁₋₃-alkyl,        di-(C₁₋₄-alkyl)-aminocarbonyl-C₁₋₃-alkyl,        aminocarbonylamino-C₁₋₃-alkyl, C₁₋₆-alkoxycarbonyl,        C₁₋₆-alkoxycarbonyl-C₁₋₃-alkyl or hydroxycarbonyl-C₁₋₃-alkyl        group,    -   a phenyl, pyridinyl or diazinyl group which may be substituted        in each case by a halogen, by a C₁₋₃-alkyl, C₁₋₃-alkoxy,        hydroxy, amino, C₁₋₄-alkyl-amino, di-(C₁₋₄-alkyl)-amino,        amino-C₁₋₃-alkyl, C₁₋₄-alkyl-amino-C₁₋₃-alkyl,        di-(C₁₋₄-alkyl)-amino-C₁₋₃-alkyl group,    -   a heterocycle selected from a 4- to 7-membered azacycloalkyl        group, a 6- to 7-membered oxaza- and diazacycloalkyl group and a        7- to 9-membered azabicycloalkyl group,        -   while the above-mentioned mono- and bicyclic heterocycles            are bound to Y¹ in formula (II) via a nitrogen or carbon            atom,        -   in the above-mentioned mono- and bicyclic heterocycles a            methylene group not directly attached to a nitrogen, oxygen            or sulphur atom may be substituted by one or two fluorine            atoms and        -   the above-mentioned mono- and bicyclic heterocycles may be            mono- or polysubstituted, for example mono- to            trisubstituted, by C₁₋₃-alkyl groups or monosubstituted by a            benzyl, cyclo-C₃₋₆-alkyl, cyclo-C₃₋₆-alkyl-C₁₋₃-alkyl,            C₁₋₄-alkylcarbonyl, hydroxy, C₁₋₄-alkoxy, amino,            C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)-amino, hydroxycarbonyl,            C₁₋₃-alkoxycarbonyl, hydroxycarbonyl-carbonyl,            C₁₋₃-alkoxycarbonyl-carbonyl, hydroxycarbonyl-C₁₋₃-alkyl,            C₁₋₃-alkoxycarbonyl-C₁₋₃-alkyl or C₁₋₃-alkylsulphonyl group,    -   or also, if Y¹ denotes the carbon atom, the hydroxycarbonyl,        aminomethyl, C₁₋₄-alkyl-aminomethyl or        di-(C₁₋₄-alkyl)-aminomethyl group,    -   R⁵ denotes a hydrogen atom, a C₁₋₃-alkyl group or, if Y¹ denotes        a nitrogen atom, it may also denote a pair of free electrons,    -   R⁶ and R⁷ which may be identical or different, in each case        denote a hydrogen atom, a C₁₋₃-alkyl group or also, if Y¹        denotes a carbon atom, a C₁₋₃-alkylamino or        di-(C₁₋₃-alkyl)-amino group, while the two C₁₋₃-alkyl groups may        be joined together forming a ring and    -   R⁸ and R⁹, which may be identical or different, in each case        denote a hydrogen atom or a C₁₋₃-alkyl group,

while, unless otherwise stated, all the alkyl, alkenyl and alkynylgroups mentioned or contained in the groups defined hereinbefore may bestraight-chain or branched, each methyne group contained in the groupsdefined hereinbefore may be substituted by a fluorine atom, eachmethylene group may be substituted by up to 2 fluorine atoms and eachmethyl group may be substituted by up to 3 fluorine atoms and two alkyland alkenyl groups bound to a nitrogen atom may be joined togetherforming a 4- to 7-membered, saturated or unsaturated heterocyclic ring,

all the aromatic and heteroaromatic groups mentioned or contained in thegroups defined hereinbefore may additionally be mono-, di- ortrisubstituted by halogen or by cyano or hydroxy groups and thesubstituents may be identical or different,

the tautomers, the isomers, the diastereomers, the enantiomers, thehydrates thereof, the mixtures thereof and the salts thereof as well asthe hydrates of the salts, particularly the physiologically acceptablesalts thereof with inorganic or organic acids or bases.

A twelfth embodiment of the present invention consists of the compoundsof the above general formula (I), wherein

A, X, D, E, G, M, Q and R¹ are defined as mentioned hereinbefore underthe first, second, third, fourth, fifth, sixth, seventh, eighth or ninthembodiment and

R² denotes the hydrogen atom or

a phenylmethyl group or a C₂₋₇-alkyl group which may be substituted inthe ω-position by a phenyl, amino, C₁₋₆-alkylamino,di-(C₁₋₆-alkyl)-amino group,

-   -   while the phenyl and phenylmethyl group mentioned hereinbefore        may additionally be mono- or disubstituted at an aromatic carbon        atom by halogen, by C₁₋₃-alkyl, C₁₋₃-alkoxy, amino-C₁₋₃-alkyl,        C₁₋₃-alkylamino-C₁₋₃-alkyl or di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl        groups and the substituents may be identical or different,

R³ denotes the hydrogen atom or a C₁₋₃-alkyl group or

R² and R³ together with the enclosed nitrogen atom denote a group ofgeneral formula

wherein

-   -   Y¹ denotes the carbon atom or, if R⁵ denotes a pair of free        electrons, it may also denote the nitrogen atom,    -   q and r, if Y¹ denotes the carbon atom, denote the numbers 0 or        1 or    -   q and r, if Y¹ denotes the nitrogen atom, denote the numbers 1        or 2,    -   R⁴ denotes the hydrogen atom, an amino, C₁₋₄-alkyl-amino,        di-(C₁₋₄-alkyl)-alkylamino, C₁₋₆-alkyl, a cyclo-C₃₋₇-alkyl or        cyclo-C₃₋₇-alkenyl group optionally substituted by a        hydroxycarbonyl, C₁₋₆-alkoxycarbonyl, hydroxycarbonyl-C₁₋₃-alkyl        or C₁₋₆-alkoxycarbonyl-C₁₋₃-alkyl group, an amino-C₂₋₇-alkyl,        C₁₋₄-alkyl-amino-C₂₋₇-alkyl, di-(C₁₋₄-alkyl-amino)-C₂₋₇-alkyl,        C₁₋₆-alkoxycarbonyl, C₁₋₆-alkoxycarbonyl-C₁₋₃-alkyl or        hydroxycarbonyl-C₁₋₃-alkyl group,    -   a phenyl or pyridyl group which may be substituted in each case        by a halogen, by a C₁₋₃-alkyl, C₁₋₃-alkoxy, amino,        C₁₋₄-alkyl-amino, di-(C₁₋₄-alkyl)-amino group,    -   a heterocycle selected from a 6- to 7-membered azacycloalkyl        group, a 6- to 7-membered S,S-dioxothiaza- and diazacycloalkyl        group and a 7- to 9-membered azabicycloalkyl group,        -   while the above-mentioned mono- and bicyclic heterocycles            are bound to Y¹ in formula (II) via a nitrogen or a carbon            atom,        -   in the above-mentioned mono- and bicyclic heterocycles a            methylene group not directly linked to a nitrogen, oxygen or            sulphur atom may be substituted by one or two fluorine atoms            and        -   the above-mentioned mono- and bicyclic heterocycles may be            mono- or disubstituted by a hydroxy, C₁₋₃-alkyl or            hydroxy-C₁₋₃-alkyl group, by a benzyl, cyclo-C₃₋₆-alkyl,            hydroxy-C₃₋₆-cycloalkyl, cyclo-C₃₋₆-alkyl-C₁₋₃-alkyl,            C₁₋₃-alkylcarbonyl-C₁₋₃-alkyl, amino, C₁₋₄-alkylamino or            di-(C₁₋₄-alkyl)-amino, hydroxycarbonyl-carbonyl,            C₁₋₆-alkoxycarbonyl-carbonyl,            hydroxycarbonyl-C₁₋₃-alkylcarbonyl,            C₁₋₃-alkoxycarbonyl-C₁₋₃-alkylcarbonyl, aminosulphonyl,            C₁₋₄-alkylaminosulphonyl, di-(C₁₋₄-alkyl)-aminosulphonyl,            cyclo-C₃₋₇-alkylsulphonyl, aminocarbonyl-C₁₋₃-alkyl,            C₁₋₄-alkylaminocarbonyl-C₁₋₃-alkyl,            di-(C₁₋₄-alkyl)-aminocarbonyl-C₁₋₃-alkyl,            hydroxyaminocarbonyl-C₁₋₃-alkyl,            C₁₋₃-alkoxyaminocarbonyl-C₁₋₃-alkyl or            hydroxy-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl groups,    -   or also, if Y¹ denotes the carbon atom, the hydroxycarbonyl,        aminomethyl, C₁₋₄-alkyl-aminomethyl or        di-(C₁₋₄-alkyl)-aminomethyl group,    -   R⁵ denotes a hydrogen atom or, if Y¹ denotes a nitrogen atom,        may also denote a pair of free electrons,    -   R⁶ and R⁷ which may be identical or different, in each case        denote a hydrogen atom, a C₁₋₃-alkyl group or also, if Y¹        denotes a carbon atom, a C₁₋₃-alkylamino or        di-(C₁₋₃-alkyl)-amino group, while the two C₁₋₃-alkyl groups may        be joined together, forming a ring and    -   R⁸ and R⁹, which may be identical or different, in each case        denote a hydrogen atom or a C₁₋₃-alkyl group,

the tautomers, the isomers, the diastereomers, the enantiomers, thehydrates thereof, the mixtures thereof and the salts thereof and thehydrates of the salts, particularly the physiologically acceptable saltsthereof with inorganic or organic acids or bases.

A thirteenth embodiment of the present invention consists of thecompounds of the above general formula (I), wherein

A, X, D, E, G, M, Q and R¹ are defined as mentioned hereinbefore underthe first, second, third, fourth, fifth, sixth, seventh, eighth or ninthembodiment and

R² denotes a phenylmethyl group or a C₂₋₇-alkyl group which may besubstituted in the ω-position by a phenyl, amino, C₁₋₆-alkylamino,di-(C₁₋₆-alkyl)-amino group,

-   -   while the phenyl and phenylmethyl group mentioned hereinbefore        may be substituted at an aromatic carbon atom by an        amino-C₁₋₃-alkyl, C₁₋₃-alkylamino-C₁₋₃-alkyl or        di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl group,

R³ denotes the hydrogen atom or a C₁₋₃-alkyl group or

R² and R³ together with the enclosed nitrogen atom denote a group ofgeneral formula

wherein

-   -   R⁶ and R⁷ in each case denote a hydrogen atom or a dimethylamino        group,    -   R⁸ and R⁹ in each case denote the hydrogen atom and        -   (a) Y¹ denotes the carbon atom,            -   q and r denote the numbers 0 or 1,            -   R⁴ denotes the hydrogen atom,            -   a phenyl, pyridinyl or pyrimidinyl group which may be                substituted in each case by a halogen, by an amino,                methylamino, dimethylamino, methyl or methoxy group,            -   a hydroxy, 2-diethylamino-ethyl, amino, methylamino,                dimethylamino, diethylamino, pyrrolidin-1-yl,                3-hydroxy-pyrrolidin-1-yl,                2-hydroxycarbonyl-pyrrolidin-1-yl,                2-methoxycarbonyl-pyrrolidin-1-yl, piperidin-1-yl,                4,4-dimethylpiperidin-1-yl,                4-amino-4-methyl-piperidin-1-yl,                2-hydroxycarbonyl-piperidin-1-yl,                2-methoxycarbonyl-piperidin-1-yl,                4-hydroxymethyl-piperidin-1-yl,                4-(1-hydroxycyclopropyl)-piperidin-1-yl,                4-amino-piperidin-1-yl, 4-methylamino-piperidin-1-yl,                4-dimethylamino-piperidin-1-yl,                4-hydroxy-4-methyl-piperidin-1-yl,                4-hydroxy-4-ethyl-piperidin-1-yl,                4-hydroxy-4-trifluoromethyl-piperidin-1-yl,                4-hydroxy-4-hydroxymethyl-piperidin-1-yl,                3-amino-piperidin-1-yl, 3-methylamino-piperidin-1-yl,                3-dimethylamino-piperidin-1-yl,                3-hydroxy-piperidin-1-yl, 4-hydroxy-piperidin-1-yl,                4-hydroxycarbonylmethyl-piperidin-1-yl,                4-ethoxycarbonylmethyl-piperidin-1-yl,                perhydro-azepin-1-yl, perhydro-1,4-diazepin-1-yl,                4-methyl-perhydro-1,4-diazepin-1-yl,                1-methyl-piperidin-4-yl, piperidin-4-yl,                1-ethylpiperidin-4-yl,                1-(2-hydroxyethyl)-piperidin-4-yl,                1-cyclopropyl-piperidin-4-yl,                1-cyclopropylmethyl-piperidin-4-yl,                1-methylsulphonyl-piperidin-4-yl,                1-ethylsulphonyl-piperidin-4-yl,                1-isopropylsulphonyl-piperidin-4-yl,                1-cyclopropylsulphonyl-piperidin-4-yl,                4-hydroxy-1-methylsulphonyl-piperidin-4-yl,                1-aminosulphonyl-piperidin-4-yl,                1-(methylaminosulphonyl)-piperidin-4-yl,                1-(dimethylaminosulphonyl)-piperidin-4-yl,                1-hydroxycarbonylmethyl-piperidin-4-yl,                1-ethoxycarbonylmethyl-piperidin-4-yl,                1-(2-hydroxycarbonylethyl)-piperidin-4-yl,                1-(2-ethoxycarbonylethyl)-piperidin-4-yl,                1-(3-hydroxycarbonyl-propionyl)-piperidin-4-yl,                1-(3-ethoxycarbonyl-propionyl)-piperidin-4-yl,                1-(hydroxycarbamoyl-methyl)-piperidin-4-yl,                1-(hydroxy-methyl-carbamoyl-methyl)-piperidin-4-yl,                1-(methoxycarbamoyl-methyl)-piperidin-4-yl,                1-oxalyl-piperidin-4-yl, 1-ethoxyoxalyl-piperidin-4-yl,                piperazin-1-yl, 4-methyl-piperazin-1-yl,                4-cyclopropylmethyl-piperazin-1-yl,                4-ethyl-piperazin-1-yl,                4-(2-hydroxyethyl)-piperazin-1-yl,                4-cyclopropyl-piperazin-1-yl,                4-methylsulphonyl-piperazin-1-yl,                4-aminosulphonyl-piperazin-1-yl,                4-(methylaminosulphonyl)-piperazin-1-yl,                4-(dimethylaminosulphonyl)-piperazin-1-yl,                4-hydroxycarbonylmethyl-piperazin-1-yl,                4-ethoxycarbonylmethyl-piperazin-1-yl,                4-(2-hydroxycarbonylethyl)-piperazin-1-yl,                4-(2-ethoxycarbonylethyl)-piperazin-1-yl,                4-(3-hydroxycarbonyl-propionyl)-piperazin-1-yl,                4-(3-ethoxycarbonyl-propionyl)-piperazin-1-yl,                4-(hydroxycarbamoyl)-methyl-piperazin-1-yl,                4-(hydroxy-methyl-carbamoyl)-methyl-piperazin-1-yl,                4-(methoxycarbamoyl)-methyl-piperazin-1-yl,                1,2-dimethyl-piperazin-1-yl, 3-methyl-piperazin-1-yl,                3,4,5-trimethyl-piperazin-1-yl,                3,5-dimethyl-piperazin-1-yl,                3,3,4-trimethyl-piperazin-1-yl,                3,3-dimethyl-piperazin-1-yl,                3,3,4,5,5-pentamethyl-piperazin-1-yl,                3,3,5,5-tetramethyl-piperazin-1-yl,                3,3,3-trifluoro-2-oxo-propyl)-piperazin-1-yl,                morpholin-4-yl, 1,1-dioxo-1λ⁶-thiomorpholin-4-yl,                tetrahydropyran-4-yl, 4,4-difluoro-piperidin-1-yl,                8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl,                8-aza-bicyclo[3.2.1]oct-3-yl, azetidin-1-yl,                1-(methoxycarbonylmethyl)-piperidin-4-yl,                1-(ethoxycarbonylmethyl)-piperidin-4-yl,                4-(ethoxycarbonylmethyl)-piperazin-1-yl,                1-hydroxycarbonylmethyl-piperidin-4-yl or                4-hydroxycarbonylmethyl-piperazin-1-yl group, and            -   R⁵ denotes a hydrogen atom, or        -   (b) Y¹ denotes a nitrogen atom,            -   q and r denote the numbers 1 or 2,            -   R⁴ denotes the hydrogen atom,            -   a phenyl, pyridinyl or pyrimidinyl group which may be                substituted in each case by a halogen, by an amino,                methylamino, dimethylamino, methyl or methoxy group,            -   a methyl, ethyl, isopropyl, cyclopropyl, cyclopentyl,                cyclohexyl, cycloheptyl,                4-hydroxycarbonylmethyl-cylohexyl,                4-ethoxycarbonylmethyl-cyclohexyl, cyclopropylmethyl,                2-diethylamino-propyl, 1-quinuclidin-3-yl,                tetrahydropyran-4-yl, 1-piperidin-4-yl,                1-methyl-piperidin-4-yl, 1-ethyl-piperidin-4-yl,                1-(2-hydroxyethyl)-piperidin-4-yl,                1-methylsulphonyl-piperidin-4-yl,                1-aminosulphonyl-piperidin-4-yl,                1-(methylaminosulphonyl)-piperidin-4-yl,                1-(dimethylaminosulphonyl)-piperidin-4-yl,                1-hydroxycarbonylmethyl-piperidin-4-yl,                1-ethoxycarbonylmethyl-piperidin-4-yl,                1-(2-hydroxycarbonylethyl)-piperidin-4-yl,                1-(2-ethoxycarbonylethyl)-piperidin-4-yl,                1-(3-hydroxycarbonyl-propionyl)-piperidin-4-yl,                1-(3-ethoxycarbonyl-propionyl)-piperidin-4-yl,                1-(hydroxycarbamoyl-methyl)-piperidin-4-yl,                1-(hydroxy-methyl-carbamoyl-methyl)-piperidin-4-yl,                1-(methoxycarbamoyl-methyl)-piperidin-4-yl,                1-cyclopropyl-piperidin-4-yl,                1-cyclopropylmethyl-piperidin-4-yl,                1-hydroxycarbonylmethyl-piperidin-4-yl or                1-ethoxycarbonylmethyl-piperidin-4-yl group and            -   R⁵ denotes a pair of free electrons,

the tautomers, the isomers, the diastereomers, the enantiomers, thehydrates thereof, the mixtures thereof and the salts thereof and thehydrates of the salts, particularly the physiologically acceptable saltsthereof with inorganic or organic acids or bases.

A fourteenth embodiment of the present invention comprises the compoundsof the above general formula (I), wherein

A, X, D, E, G, M, Q and R¹ are defined as mentioned hereinbefore underthe first, second, third, fourth, fifth, sixth, seventh, eighth or ninthembodiment and

R² denotes a phenylmethyl group or a C₂₋₇-alkyl group which may besubstituted in the ω-position by a phenyl, amino, C₁₋₆-alkylamino,di-(C₁₋₆-alkyl)-amino group,

-   -   while the above-mentioned phenyl and phenylmethyl group may be        substituted at an aromatic carbon atom by an amino-C₁₋₃-alkyl,        C₁₋₃-alkylamino-C₁₋₃-alkyl or    -   di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl group,

R³ denotes the hydrogen atom or a C₁₋₃-alkyl group or

R² and R³ together with the enclosed nitrogen atom denote a group ofgeneral formula

wherein

-   -   R⁶ and R⁷ in each case denote a hydrogen atom or a dimethylamino        group,    -   R⁸ and R⁹ in each case denote the hydrogen atom and        -   (a) Y¹ denotes the carbon atom,            -   q and r denote the numbers 0 or 1,            -   R⁴ denotes the hydrogen atom,            -   a phenyl, pyridinyl or pyrimidinyl group which may be                substituted in each case by a halogen or by an amino,                methylamino, dimethylamino, methyl or methoxy group,            -   a hydroxy, 2-diethylamino-ethyl, amino, methylamino,                dimethylamino, diethylamino, pyrrolidin-1-yl,                piperidin-1-yl, 4_amino-piperidin-1-yl,                4-methylamino-piperidin-1-yl,                4-dimethylamino-piperidin-1-yl, 3-amino-piperidin-1-yl,                3-methylamino-piperidin-1-yl,                3-dimethylamino-piperidin-1-yl, perhydro-azepin-1-yl,                perhydro-1,4-diazepin-1-yl,                4-methyl-perhydro-1,4-diazepin-1-yl,                1-methyl-piperidin-4-yl, piperidin-4-yl,                1-ethylpiperidin-4-yl, 1-cyclopropyl-piperidin-4-yl,                1-cyclopropylmethyl-piperidin-4-yl, piperazin-1-yl,                4-methyl-piperazin-1-yl,                4-cyclopropylmethyl-piperazin-1-yl,                4-ethyl-piperazin-1-yl, 4-cyclopropyl-piperazin-1-yl,                1,2-dimethyl-piperazin-1-yl, 3-methyl-piperazin-1-yl,                3,4,5-trimethyl-piperazin-1-yl,                3,5-dimethyl-piperazin-1-yl,                3,3,4-trimethyl-piperazin-1-yl,                3,3-dimethyl-piperazin-1-yl,                3,3,4,5,5-pentamethyl-piperazin-1-yl,                3,3,5,5-tetramethyl-piperazin-1-yl, morpholin-4-yl,                4,4-difluoro-piperidin-1-yl,                8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl,                8-aza-bicyclo[3.2.1]oct-3-yl, azetidin-1-yl,                1-(methoxycarbonylmethyl)-piperidin-4-yl,                1-(ethoxycarbonylmethyl)-piperidin-4-yl,                4-(ethoxycarbonylmethyl)-piperazin-1-yl,                1-hydroxycarbonylmethyl-piperidin-4-yl or                4-hydroxycarbonylmethyl-piperazin-1-yl group, and            -   R⁵ denotes a hydrogen atom, or        -   (b) Y¹ denotes a nitrogen atom,            -   q and r denote the numbers 1 or 2,            -   R⁴ denotes the hydrogen atom,            -   a phenyl, pyridinyl or pyrimidinyl group which may be                substituted in each case by a halogen or by an amino,                methylamino, dimethylamino, methyl or methoxy group,            -   a methyl, ethyl, isopropyl, cyclopropyl,                cyclopropylmethyl, 2-diethylamino-propyl,                1-quinuclidin-3-yl, 1-piperidin-4-yl,                1-methyl-piperidin-4-yl, 1-ethyl-piperidin-4-yl,                1-cyclopropyl-piperidin-4-yl,                1-cyclopropylmethyl-piperidin-4-yl,                1-hydroxycarbonylmethyl-piperidin-4-yl or                1-ethoxycarbonylmethyl-piperidin-4-yl group and            -   R⁵ denotes a pair of free electrons,

the tautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof as well as the hydrates of thesalts, particularly the physiologically acceptable salts thereof withinorganic or organic acids or bases.

A fifteenth embodiment of the present invention consists of thecompounds of the above general formula (I), wherein

D, E, G, M, Q, R¹, R² and R³ are defined as mentioned hereinbefore underthe first, second, third, fourth, fifth, sixth, seventh, eighth, ninth,tenth, eleventh, twelfth or thirteenth embodiment and

A and X in each case denote an oxygen atom,

the tautomers, the isomers, the diastereomers, the enantiomers, thehydrates thereof, the mixtures thereof and the salts thereof and thehydrates of the salts, particularly the physiologically acceptable saltsthereof with inorganic or organic acids or bases.

A sixteenth embodiment of the present invention consists of thecompounds of the above general formula (I), wherein

A and X in each case denote an oxygen atom,

R¹ denotes a 1,3,4,5-tetrahydro-1,3-benzodiazepin-2-on-3-yl,3,4-dihydro-1H-quinazolin-2-on-3-yl,5_phenyl-2,4-dihydro-1,2,4-triazol-3-on-2-yl,1,3-dihydro-imidazo[4,5-c]quinolin-2-on-3-yl,1,3-dihydro-naphth[1,2-d]imidazol-2-on-3-yl,1,3-dihydro-benzimidazol-2-on-3-yl,4-phenyl-1,3-dihydro-imidazol-2-on-1-yl,3,4-dihydro-1H-thieno-[3,2-d]pyrimidin-2-on-3-yl or3,4-dihydro-1H-thieno[3,4-d]pyrimidin-2-on-3-yl group,

and R² and R³ are defined as mentioned hereinbefore under the first orsecond embodiment,

-   -   while the heterocycles in the carbon skeleton mentioned        hereinbefore under R¹ may additionally be monosubstituted by a        methoxy group,

and all the aromatic and heteroaromatic groups and parts of moleculesmentioned or contained in the groups defined under R¹ may additionallybe mono-, di- or trisubstituted by halogen atoms, by cyano or hydroxygroups and the substituents may be identical or different,

and in this and all the preceding embodiments in each case particularimportance attaches to the compounds wherein

D and E in each case denote a methyne group,

G denotes a methyne group substituted by the group R^(a),

M denotes a methyne group substituted by the group R^(b),

Q denotes a methyne group substituted by the group R^(c) and

R^(a), R^(b) and R^(c) independently of one another in each case denotea hydrogen or halogen atom, a C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl,cyclo-C₃₋₆-alkyl, cyclo-C₃₋₆-alkenyl, cyano, hydroxy,hydroxy-C₁₋₂-alkyl, hydroxy-C₃-alkenyl, hydroxy-C₃-alkynyl, C₁₋₄-alkoxy,C₁₋₄-alkoxy-C₁₋₂-alkyl, amino, C₁₋₄-alkyl-amino, C₃₋₄-alkenyl-amino,C₃₋₄-alkynyl-amino, di-(C₁₋₄-alkyl)-amino, di-(C₃₋₄-alkenyl)-amino,di-(C₃₋₄-alkynyl)-amino, amino-C₁₋₂-alkyl, C₁₋₃-alkyl-amino-C₁₋₂-alkyl,di-(C₁₋₃-alkyl)-amino-C₁₋₂-alkyl, amino-C₃-alkenyl,C₁₋₃-alkyl-amino-C₃-alkenyl, di-(C₁₋₃-alkyl)-amino-C₃-alkenyl,amino-C₃-alkynyl, C₁₋₃-alkyl-amino-C₃-alkynyl,di-(C₁₋₃-alkyl)-amino-C₃-alkynyl, hydroxycarbonyl, C₁₋₄-alkyl-carbonyl,formyl, C₁₋₄-alkoxy-carbonyl, aminocarbonyl, C₁₋₄-alkyl-aminocarbonyl,di-(C₁₋₄-alkyl)-aminocarbonyl, formylamino, C₁₋₄-alkyl-carbonylamino,formyl-C₁₋₄-alkyl-amino, C₁₋₄-alkyl-carbonyl-C₁₋₄-alkyl-amino,C₁₋₄-alkyl-sulphonyl, C₁₋₄-alkyl-sulphinyl, C₁₋₄-alkyl-sulphonylamino,C₁₋₄-alkyl-sulphonyl-C₁₋₄-alkylamino, aminosulphonyl,C₁₋₄-alkylaminosulphonyl or di-(C₁₋₄-alkyl)-aminosulphonyl group,

while any alkyl, alkenyl and alkynyl groups mentioned or contained inthe definitions of the groups R^(a), R^(b) and R^(c) may bestraight-chain or branched, every methyne group contained in thesegroups may be substituted by a fluorine atom, every methylene group maybe substituted by up to 2 fluorine atoms and every methyl group may besubstituted by up to 3 fluorine atoms and

the double and triple bonds of the C₃₋₄-alkenyl or C₃₋₄-alkynyl groupscontained in the groups defined for R^(a), R^(b) and R^(c) hereinbeforemay be isolated from any heteroatoms optionally also contained in thesegroups,

exceptional importance attaches to the compounds wherein

D and E in each case denote a methyne group,

G denotes a methyne group substituted by the group R^(a),

M denotes a methyne group substituted by the group R^(b),

Q denotes a methyne group substituted by the group R^(c) and

R^(a), R^(b) and R^(c) independently of one another in each case denotea hydrogen or halogen atom, a C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl,cyclo-C₃₋₆-alkyl, cyclo-C₃₋₆-alkenyl, cyano, hydroxy,hydroxy-C₁₋₂-alkyl, C₁₋₄-alkoxy, amino, C₁₋₄-alkyl-amino,di-(C₁₋₄-alkyl)-amino, amino-C₁₋₂-alkyl, C₁₋₃-alkyl-amino-C₁₋₂-alkyl,di-(C₁₋₃-alkyl)-amino-C₁₋₂-alkyl, hydroxycarbonyl, C₁₋₄-alkyl-carbonyl,formyl, C₁₋₄-alkoxy-carbonyl, aminocarbonyl, C₁₋₄-alkyl-aminocarbonyl,di-(C₁₋₄-alkyl)-aminocarbonyl, formylamino, C₁₋₄-alkyl-carbonylamino,formyl-C₁₋₄-alkyl-amino or C₁₋₄-alkyl-carbonyl-C₁₋₄-alkyl-amino group,

while any alkyl, alkenyl and alkynyl groups mentioned or contained inthe definitions of the groups R^(a), R^(b) and R^(c) may bestraight-chain or branched and every methyne group contained in thesegroups may be substituted by a fluorine atom, every methylene group maybe substituted by up to 2 fluorine atoms and every methyl group may besubstituted by up to 3 fluorine atoms, and

most particularly outstanding importance attaches to the compoundswherein

D and E in each case denote a methyne group,

G denotes a methyne group substituted by the group R^(a),

M denotes a methyne group substituted by the group R^(b),

Q denotes a methyne group substituted by the group R^(c) and

R^(a), R^(b) and R^(c) independently of one another in each case denotea hydrogen or halogen atom, a methyl, difluoromethyl, trifluoromethyl,ethyl, vinyl, ethynyl, cyano, hydroxy, methoxy, difluoromethoxy,trifluoromethoxy, amino, methylamino or dimethylamino group,

the tautomers, the isomers, the diastereomers, the enantiomers, thehydrates thereof, the mixtures thereof and the salts thereof and thehydrates of the salts, particularly the physiologically acceptable saltsthereof with inorganic or organic acids or bases.

A seventeenth embodiment of the present invention consists of thecompounds of the above general formula (I), wherein

A and X in each case denote an oxygen atom,

R¹ is defined as mentioned hereinbefore under the fifth embodiment,

D and E in each case denote a methyne group,

G denotes a methyne group substituted by the group R^(a),

M denotes a methyne group substituted by the group R^(b),

Q denotes a methyne group substituted by the group R^(c) and

R^(a), R^(b) and R^(c) independently of one another in each case denotea hydrogen or halogen atom, a methyl, difluoromethyl, trifluoromethyl,ethyl, vinyl, ethynyl, cyano, hydroxy, methoxy, difluoromethoxy,trifluoromethoxy, amino, methylamino or dimethylamino group,

while in this and all the preceding embodiments in each case outstandingimportance attaches to the compounds wherein

R² and R³ are defined as mentioned hereinbefore under the tenth oreleventh embodiment,

particularly exceptional importance attaches to the compounds wherein R²and R³ are defined as mentioned hereinbefore under the twelfthembodiment,

and most particularly oustanding importance attaches to the compoundswherein R² and R³ are defined as mentioned hereinbefore under thethirteenth embodiment,

the tautomers, the isomers, the diastereomers, the enantiomers, thehydrates thereof, the mixtures thereof and the salts thereof and thehydrates of the salts, particularly the physiologically acceptable saltsthereof with inorganic or organic acids or bases.

An eighteenth embodiment of the present invention consists of thecompounds of the above general formula (I), wherein

A and X in each case denote an oxygen atom,

D and E in each case denote a methyne group,

G denotes a methyne group substituted by the group R^(a),

M denotes a methyne group substituted by the group R^(b),

Q denotes a methyne group substituted by the group R^(c),

R^(a), R^(b) and R^(c) independently of one another in each case denotea hydrogen or halogen atom, a C₁₋₃-alkyl, trifluoromethyl, cyano,hydroxy, methoxy, trifluoromethoxy, amino, methylamino or dimethylaminogroup,

R¹ denotes a monounsaturated 5- to 7-membered diaza heterocycle, linkedto the piperidine ring in formula (I) via a nitrogen atom,

-   -   while the heterocycle mentioned hereinbefore contains a carbonyl        group adjacent to a nitrogen atom and the carbonyl group is        preferably linked to two nitrogen atoms and    -   the olefinic double bond of the heterocycle is fused to a phenyl        or thienyl ring and the phenyl and thienyl ring may be mono-,        di- or trisubstituted by halogen atoms, by methyl, methoxy,        difluoromethyl, trifluoromethyl, hydroxy, amino,        C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, acetylamino, acetyl,        cyano, difluoromethoxy or trifluoromethoxy groups, while the        substituents may be identical or different, but is preferably        unsubstituted or monosubstituted by a halogen atom, by a methyl        or methoxy group,

and definitions of R¹ include for example a1,3,4,5-tetrahydro-1,3-benzodiazepin-2-on-3-yl,3,4-dihydro-1H-quinazolin-2-on-3-yl,5-phenyl-2,4-dihydro-1,2,4-triazol-3-on-2-yl,1,3-dihydro-imidazo[4,5-c]quinolin-2-on-3-yl,1,3-dihydro-naphth[1,2-d]imidazol-2-on-3-yl,1,3-dihydro-benzimidazol-2-on-3-yl,4-phenyl-1,3-dihydro-imidazol-2-on-1-yl,3,4-dihydro-1H-thieno[3,2-d]pyrimidin-2-on-3-yl or3,4-dihydro-1H-thieno[3,4-d]pyrimidin-2-on-3-yl group which is mono-,di- or trisubstituted at an unsaturated carbon atom of the aromatic orheteroaromatic moiety by halogen atoms or by cyano or hydroxy groups andthe substituents may be identical or different, but are preferablyunsubstituted,

R² and R³ together with the enclosed nitrogen atom denote a group ofgeneral formula

wherein

-   -   Y¹ denotes the carbon atom or, if R⁵ denotes a pair of free        electrons, it may also denote the nitrogen atom,    -   q and r, if Y¹ denotes the carbon atom, denote the numbers 0, 1        or 2, while the total of q and r is 1, 2 or 3,    -   q and r, if Y¹ denotes the nitrogen atom, denote the numbers 1        or 2, while the total of q and r is 2 or 3,    -   R⁴ denotes the hydrogen atom, an amino, C₁₋₄-alkyl-amino,        di-(C₁₋₄-alkyl)-alkylamino, C₁₋₆-alkyl, a cyclo-C₃₋₇-alkyl,        amino-C₂₋₇-alkyl, C₁₋₄-alkyl-amino-C₂₋₇-alkyl,        di-(C₁₋₄-alkyl-amino)-C₂₋₇-alkyl, C₁₋₆-alkoxycarbonyl,        C₁₋₆-alkoxycarbonyl-C₁₋₃-alkyl or hydroxycarbonyl-C₁₋₃-alkyl        group optionally substituted by a hydroxycarbonyl,        C₁₋₆-alkoxycarbonyl, hydroxycarbonyl-C₁₋₃-alkyl or        C₁₋₆-alkoxycarbonyl-C₁₋₃-alkyl group,    -   a phenyl or pyridyl group which may be substituted in each case        by a halogen atom, by a C₁₋₃-alkyl, C₁₋₃-alkoxy, amino,        C₁₋₄-alkyl-amino or di-(C₁₋₄-alkyl)-amino group,    -   a heterocycle selected from a 5- to 7-membered azacycloalkyl or        S,S-dioxothiaza group and a 6- to 7-membered diazacycloalkyl        group,        -   while the above-mentioned heterocycles are bound to Y¹ in            formula (II) via a nitrogen or a carbon atom and        -   may be substituted by one or two hydroxy, C₁₋₃-alkyl or            hydroxy-C₁₋₃-alkyl groups or by a cyclo-C₃₋₆-alkyl,            hydroxy-C₃₋₆-cycloalkyl, cyclo-C₃₋₆-alkyl-C₁₋₃-alkyl,            C₁₋₃-alkylcarbonyl-C₁₋₃-alkyl, amino, C₁₋₄-alkylamino,            di-(C₁₋₄-alkyl)-amino, hydroxycarbonyl-carbonyl,            C₁₋₃-alkoxycarbonyl-carbonyl,            hydroxycarbonyl-C₁₋₃-alkylcarbonyl,            C₁₋₃-alkoxycarbonyl-C₁₋₃-alkylcarbonyl, aminosulphonyl,            C₁₋₄-alkylaminosulphonyl, di-(C₁₋₄-alkyl)-aminosulphonyl,            cyclo-C₃₋₇-alkyl-sulphonyl, aminocarbonyl-C₁₋₃-alkyl,            C₁₋₄-alkylaminocarbonyl-C₁₋₃-alkyl,            di-(C₁₋₄-alkyl)-aminocarbonyl-C₁₋₃-alkyl,            hydroxyaminocarbonyl-C₁₋₃-alkyl,            C₁₋₃-alkoxyaminocarbonyl-C₁₋₃-alkyl or            hydroxy-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl group,    -   R⁵ denotes a hydrogen atom or, if Y¹ denotes a nitrogen atom, it        may also denote a pair of free electrons and    -   R⁶, R⁷, R⁸ and R⁹, which may be identical or different, in each        case denote a hydrogen atom or a C₁₋₃-alkyl group,

the tautomers, the isomers, the diastereomers, the enantiomers, thehydrates thereof, the mixtures thereof and the salts thereof and thehydrates of the salts, particularly the physiologically acceptable saltsthereof with inorganic or organic acids or bases.

A nineteenth embodiment of the present invention consists of thecompounds of the above general formula (I), wherein

A and X in each case denote an oxygen atom,

D and E in each case denote a methyne group,

G denotes a methyne group substituted by the group R^(a),

M denotes a methyne group substituted by the group R^(b),

Q denotes a methyne group substituted by the group R^(c),

R^(a), R^(b) and R^(c) independently of one another in each case denotea hydrogen or halogen atom, a C₁₋₃-alkyl, trifluoromethyl, cyano,hydroxy, methoxy, trifluoromethoxy, amino, methylamino or dimethylaminogroup,

R¹ denotes a monounsaturated 5- to 7-membered diaza heterocycle, linkedto the piperidine ring in formula (I) via a nitrogen atom,

-   -   while the above-mentioned heterocycle contains a carbonyl group        adjacent to a nitrogen atom and the carbonyl group is preferably        linked to two nitrogen atoms and    -   the olefinic double bond of the heterocycle is fused to a phenyl        or thienyl ring and the phenyl and thienyl ring may be mono-,        di- or trisubstituted by halogen atoms, by methyl, methoxy,        difluoromethyl, trifluoromethyl, hydroxy, amino,        C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, acetylamino, acetyl,        cyano, difluoromethoxy or trifluoromethoxy groups, while the        substituents may be identical or different, but is preferably        unsubstituted or monosubstituted by a halogen atom or by a        methyl or methoxy group,

and examples of definitions of R¹ include a1,3,4,5-tetrahydro-1,3-benzodiazepin-2-on-3-yl,3,4-dihydro-1H-quinazolin-2-on-3-yl,5-phenyl-2,4-dihydro-1,2,4-triazol-3-on-2-yl,1,3-dihydro-imidazo[4,5-c]quinolin-2-on-3-yl,1,3-dihydro-naphth[1,2-d]imidazol-2-on-3-yl,1,3-dihydro-benzimidazol-2-on-3-yl,4-phenyl-1,3-dihydro-imidazol-2-on-1-yl,3,4-dihydro-1H-thieno[3,2-d]pyrimidin-2-on-3-yl or3,4-dihydro-1H-thieno[3,4-d]pyrimidin-2-on-3-yl group, which may bemono-, di- or trisubstituted at an unsaturated carbon atom of thearomatic or heteroaromatic moiety by halogen atoms or by cyano orhydroxy groups and the substituents may be identical or different, butare preferably unsubstituted,

R² and R³ together with the enclosed nitrogen atom denote a group ofgeneral formula

wherein

-   -   Y¹ denotes the carbon atom or, if R⁵ denotes a pair of free        electrons, it may also denote the nitrogen atom,    -   q and r, if Y¹ denotes the carbon atom, denote the numbers 0, 1        or 2, the sum of q and r being 1, 2 or 3,    -   q and r, if Y¹ denotes the nitrogen atom, denote the numbers 1        or 2, the sum of q and r being 2 or 3,    -   R⁴ denotes the hydrogen atom, an amino, C₁₋₄-alkyl-amino,        di-(C₁₋₄-alkyl)-alkylamino, C₁₋₆-alkyl, cyclo-C₃₋₇-alkyl,        amino-C₂₋₇-alkyl, C₁₋₄-alkyl-amino-C₂₋₇-alkyl,        di-(C₁₋₄-alkyl-amino)-C₂₋₇-alkyl, C₁₋₆-alkoxycarbonyl,        C₁₋₆-alkoxycarbonyl-C₁₋₃-alkyl or hydroxycarbonyl-C₁₋₃-alkyl        group,    -   a phenyl or pyridyl group which may be substituted in each case        by a halogen atom or by a C₁₋₃-alkyl, C₁₋₃-alkoxy, amino,        C₁₋₄-alkyl-amino or di-(C₁₋₄-alkyl)-amino group,    -   a heterocycle selected from a 5- to 7-membered azacycloalkyl        group and a 6- to 7-membered diazacycloalkyl group,        -   while the above-mentioned heterocycles are bound to Y¹ in            formula (II) via a nitrogen or carbon atom and        -   may be substituted by a C₁₋₃-alkyl, cyclo-C₃₋₆-alkyl,            cyclo-C₃₋₆-alkyl-C₁₋₃-alkyl, amino, C₁₋₄-alkylamino or            di-(C₁₋₄-alkyl)-amino group,    -   R⁵ denotes a hydrogen atom or, if Y¹ denotes a nitrogen atom, it        may also denote a pair of free electrons and    -   R⁶, R⁷, R⁸ and R⁹, which may be identical or different, in each        case denote a hydrogen atom or a C₁₋₃-alkyl group,

the tautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof as well as the hydrates of thesalts, particularly the physiologically acceptable salts thereof withinorganic or organic acids or bases.

The following compounds are mentioned by way of example as mostparticularly preferred compounds of the above general formula (I):

No. Structure Name (1)

(R)-1-(3,4-dibromo-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(2)

(R)-1-(3,4-dibromo-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(3)

(R)-1-(3,4-dibromo-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(4)

(R)-1-(3,4-dibromo-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(5)

(R)-1-(3,4-dibromo-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(6)

(R)-2-(4,4′-bipiperidinyl-1-yl)-1-(3,4-dibromo-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(7)

(R)-2-(1,4′-bipiperidinyl-1-yl)-1-(3,4-dibromo-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(8)

(R)-1-(3,4-dibromo-benzyl)-2-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(9)

(R)-1-(3,4-dibromo-benzyl)-2-oxo-2-(4-perhydro-1,4-diazepin-1-yl)-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(10)

(R)-1-(3,4-dibromo-benzyl)-2-oxo-2-(4-perhydro-azepin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(11)

(R)-1-(3,4-dibromo-benzyl)-2-oxo-2-(4-pyrrolidin-1-yl)-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(12)

(R)-1-(3,4-dibromo-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-perhydro-1,4-diazepin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(13)

4(R)-1-(3,4-dibromo-benzyl)-2-oxo-2-(4-piperidin-4-yl-perhydro-1,4-diazepin-1-yl)-ethyl-(2-oxo-1,2,4,5-tetrahydro-1,3-benzo-diazepin-3-yl)-piperidine-1-carboxylate(14)

(R)-1-(3,4-dibromo-benzyl)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(15)

(R)-1-(3,4-dibromo-benzyl)-2-(4-methyl-amino-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(16)

(R)-1-(3,4-dibromo-benzyl)-2-(4-amino-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(17)

(R)-1-(3,4-dibromo-benzyl)-2-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(18)

(R)-1-(3,4-dibromo-benzyl)-2-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(19)

(R)-1-(3,4-dibromo-benzyl)-2-oxo-2-(4-pyridin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(20)

(R)-1-(3,4-dibromo-benzyl)-2-oxo-2-(3,4,5,6-tetrahydro-2H-4,4′-bipyridinyl-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(21)

(R)-1-(3,4-dibromo-benzyl)-2-[4-(4-ethyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(22)

(R)-2-[4-(4-cyclopropylmethyl-piperazin-1-yl)-piperidin-1-yl]-1-(3,4-dibromo-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(23)

(R)-1-(3,4-dibromo-benzyl)-2-[4-(4-isopropyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(24)

(R)-2-[4-(4-cyclopropyl-piperazin-1-yl)-piperidin-1-yl]-1-(3,4-dibromo-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(25)

(R)-2-[4-(1-cyclopropyl-piperidin-4-yl)-piperazin-1-yl]-1-(3,4-dibromo-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(26)

(R)-1-(3,4-dibromo-benzyl)-2-[4-(4-methoxycarbonylmethyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(27)

(R)-2-[4-(4-carboxymethyl-piperazin-1-yl)-piperidin-1-yl]-1-(3,4-dibromo-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(28)

(R)-2-[4-(2-amino-pyrimidine-5-yl)-piperazin-1-yl]-1-(3,4-dibromo-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (29)

(R)-1-(3,4-dibromo-benzyl)-2-[4-(2-diethylamino-ethyl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(30)

(R)-1-(3,4-dibromo-benzyl)-2-[4-(3-dimethylamino-propyl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(31)

(R)-1-(3,4-dichloro-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(32)

(R)-1-(3,4-dichloro-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(33)

(R)-1-(3,4-dichloro-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(34)

(R)-1-(3,4-dichloro-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(35)

(R)-1-(3,4-dichloro-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(36)

(R)-2-(4,4′-bipiperidinyl-1-yl)-1-(3,4-dichloro-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(37)

(R)-2-(1,4′-bipiperidinyl-1′-yl)-1-(3,4-dichloro-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(38)

(R)-1-(3,4-dichloro-benzyl)-2-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(39)

(R)-1-(3,4-dichloro-benzyl)-2-oxo-2-(4-perhydro-1,4-diazepin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(40)

(R)-1-(3,4-dichloro-benzyl)-2-oxo-2-(4-perhydro-azepin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(41)

(R)-1-(3,4-dichloro-benzyl)-2-oxo-2-(4-pyrrolidin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(42)

(R)-1-(3,4-dichloro-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-perhydro-1,4-diazepin-1-yl-]2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(43)

(R)-1-(3,4-dichloro-benzyl)-2-oxo-2-(4-piperidin-4-yl-perhydro-1,4-diazepin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(44)

(R)-1-(3,4-dichloro-benzyl)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(45)

(R)-1-(3,4-dichloro-benzyl)-2-(4-methylamino-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(46)

(R)-1-(3,4-dichloro-benzyl)-2-(4-amino-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(47)

(R)-1-(3,4-dichloro-benzyl)-2-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(48)

(R)-1-(3,4-dichloro-benzyl)-2-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(49)

(R)-1-(3,4-dichloro-benzyl)-2-oxo-2-(4-pyridin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(50)

(R)-1-(3,4-dichloro-benzyl)-2-oxo-2-(3,4,5,6-tetrahydro-2H-4,4′-bipyridinyl-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(51)

(R)-1-(3,4-dichloro-benzyl)-2-[4-(4-ethyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(52)

(R)-2-[4-(4-cyclopropylmethyl-piperazin-1-yl)-piperidin-1-yl]-1-(3,4-dichloro-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(53)

(R)-1-(3,4-dichloro-benzyl)-2-[4-(4-isopropyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(54)

(R)-2-[4-(4-cyclopropyl-piperazin-1-yl)-piperidin-1-yl]-1-(3,4-dichloro-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(55)

(R)-2-[4-(1-cyclopropyl-piperidin-4-yl)-piperazin-1-yl]-1-(3,4-dichloro-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(56)

(R)-1-(3,4-dichloro-benzyl)-2-[4-(4-methoxycarbonylmethyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(57)

(R)-2-[4-(4-carboxymethyl-piperazin-1-yl)-piperidin-1-yl]-1-(3,4-dichloro-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(58)

(R)-2-[4-(2-amino-pyrimidine-5-yl)-piperazin-1-yl]-1-(3,4-dichloro-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(59)

(R)-1-(3,4-dichloro-benzyl)-2-[4-(2-diethylamino-ethyl)-piperidin-1-yl]-2-oxo-ethyl4(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(60)

(R)-1-(3,4-dichloro-benzyl)-2-[4-(3-dimethylamino-propyl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(61)

(R)-1-(4-bromo-3,5-dimethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(62)

(R)-1-(4-bromo-3,5-dimethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(63)

(R)-1-(4-bromo-3,5-dimethyl-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(64)

(R)-1-(4-bromo-3,5-dimethyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(65)

(R)-1-(4-bromo-3,5-dimethyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(66)

(R)-2-(4,4′-bipiperidinyl-1-yl)-1-(4-bromo-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(67)

(R)-2-(1,4′-bipiperidinyl-1′-yl)-1-(4-bromo-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(68)

(R)-1-(4-bromo-3,5-dimethyl-benzyl)-2-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(69)

(R)-1-(4-bromo-3,5-dimethyl-benzyl)-2-oxo-2-(4-perhydro-1,4-diazepin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(70)

(R)-1-(4-bromo-3,5-dimethyl-benzyl)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(71)

(R)-1-(4-chloro-3,5-dimethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(72)

(R)-1-(4-chloro-3,5-dimethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(73)

(R)-1-(4-chloro-3,5-dimethyl-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(74)

(R)-1-(4-chloro-3,5-dimethyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(75)

(R)-1-(4-chloro-3,5-dimethyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(76)

(R)-2-(4,4′-bipiperidinyl-1-yl)-1-(4-chloro-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(77)

(R)-2-(1,4′-bipiperidinyl-1′-yl)-1-(4-chloro-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(78)

(R)-1-(4-chloro-3,5-dimethyl-benzyl)-2-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(79)

(R)-1-(4-chloro-3,5-dimethyl-benzyl)-2-oxo-2-(4-perhydro-1,4-diazepin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(80)

(R)-1-(4-chloro-3,5-dimethyl-benzyl)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(81)

(R)-1-(3,5-dibromo-4-methyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(82)

(R)-1-(3,5-dibromo-4-methyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(83)

(R)-1-(3,5-dibromo-4-methyl-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(84)

(R)-1-(3,5-dibromo-4-methyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(85)

(R)-1-(3,5-dibromo-4-methyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(86)

(R)-2-(4,4′-bipiperidinyl-1-yl)-1-(3,5-dibromo-4-methyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(87)

(R)-2-(1,4′-bipiperidinyl-1′-yl)-1-(3,5-dibromo-4-methyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(88)

(R)-1-(3,5-dibromo-4-methyl-benzyl)-2-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(89)

(R)-1-(3,5-dibromo-4-methyl-benzyl)-2-oxo-2-(4-perhydro-1,4-diazepin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(90)

(R)-1-(3,5-dibromo-4-methyl-benzyl)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(91)

(R)-1-(3,5-dichloro-4-methyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(92)

(R)-1-(3,5-dichloro-4-methyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(93)

(R)-1-(3,5-dichloro-4-methyl-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(94)

(R)-1-(3,5-dichloro-4-methyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(95)

(R)-1-(3,5-dichloro-4-methyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(96)

(R)-2-(4,4′-bipiperidinyl-1-yl)-1-(3,5-dichloro-4-methyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(97)

(R)-2-(1,4′-bipiperidinyl-1′-yl)-1-(3,5-dichloro-4-methyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(98)

(R)-1-(3,5-dichloro-4-methyl-benzyl)-2-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(99)

(R)-1-(3,5-dichloro-4-methyl-benzyl)-2-oxo-2-(4-perhydro-1,4-diazepin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(100)

(R)-1-(3,5-dichloro-4-methyl-benzyl)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(101)

(R)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-1-(3,4,5-trimethyl-benzyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(102)

(R)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-1-(3,4,5-trimethyl-benzyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(103)

(R)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-1-(3,4,5-trimethyl-benzyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(104)

(R)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-1-(3,4,5-trimethyl-benzyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(105)

(R)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-1-(3,4,5-trimethyl-benzyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(106)

(R)-2-(4,4′-bipiperidinyl-1-yl)-2-oxo-1-(3,4,5-trimethyl-benzyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(107)

(R)-2-(1,4′-bipiperidinyl-1′-yl)-2-oxo-1-(3,4,5-trimethyl-benzyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(108)

(R)-2-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-2-oxo-1-(3,4,5-trimethyl-benzyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(109)

(R)-2-oxo-2-(4-perhydro-1,4-diazepin-1-yl-piperidin-1-yl)-1-(3,4,5-trimethyl-benzyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(110)

(R)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-1-(3,4,5-trimethyl-benzyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(111)

(R)-1-(3,5-dibromo-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(112)

(R)-1-(3,5-dibromo-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(113)

(R)-1-(3,5-dibromo-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(114)

(R)-1-(3,5-dibromo-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(115)

(R)-1-(3,5-dibromo-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(116)

(R)-2-(4,4′-bipiperidinyl-1-yl)-1-(3,5-dibromo-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(117)

(R)-2-(1,4′-bipiperidinyl-1′-yl)-1-(3,5-dibromo-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(118)

(R)-1-(3,5-dibromo-benzyl)-2-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(119)

(R)-1-(3,5-dibromo-benzyl)-2-oxo-2-(4-perhydro-1,4-diazepin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(120)

(R)-1-(3,5-dibromo-benzyl)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(121)

(R)-1-(3,5-dimethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(122)

(R)-1-(3,5-dimethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(123)

(R)-1-(3,5-dimethyl-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(124)

(R)-1-(3,5-dimethyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(125)

(R)-1-(3,5-dimethyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(126)

(R)-2-(4,4′-bipiperidinyl-1-yl)-1-(3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(127)

(R)-2-(1,4′-bipiperidinyl-1′-yl)-1-(3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(128)

(R)-1-(3,5-dimethyl-benzyl)-2-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(129)

(R)-1-(3,5-dimethyl-benzyl)-2-oxo-2-(4-perhydro-1,4-diazepin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(130)

(R)-2-(4-dimethylamino-piperidin-1-yl)-1-(3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(131)

(R)-1-(3,5-dichloro-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(132)

(R)-1-(3,5-dichloro-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(133)

(R)-1-(3,5-dichloro-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(134)

(R)-1-(3,5-dichloro-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(135)

(R)-1-(3,5-dichloro-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(136)

(R)-2-(4,4′-bipiperidinyl-1-yl)-1-(3,5-dichloro-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(137)

(R)-2-(1,4′-bipiperidinyl-1′-yl)-1-(3,5-dichloro-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(138)

(R)-1-(3,5-dichloro-benzyl)-2-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(139)

(R)-1-(3,5-dichloro-benzyl)-2-oxo-2-(4-perhydro-1,4-diazepin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(140)

(R)-1-(3,5-dichloro-benzyl)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(141)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazenin-3-yl)-piperidine-1-carboxylate(142)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(143)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(144)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(145)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(146)

(R)-2-(4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(147)

(R)-2-(1,4′-bipiperidinyl-1′-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(148)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(149)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-(4-perhydro-1,4-diazepin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(150)

(R)-2-(4-dimethylamino-piperidin-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(151)

(R)-1-(4-methoxy-3,5-dimethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(152)

(R)-1-(4-methoxy-3,5-dimethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(153)

(R)-1-(4-methoxy-3,5-dimethyl-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(154)

(R)-1-(4-methoxy-3,5-dimethyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(155)

(R)-1-(4-methoxy-3,5-dimethyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(156)

(R)-2-(4,4′-bipiperidinyl-1-yl)-1-(4-methoxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(157)

(R)-2-(1,4′-bipiperidinyl-1′-yl)-1-(4-methoxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(158)

(R)-1-(4-methoxy-3,5-dimethyl-benzyl)-2-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(159)

(R)-1-(4-methoxy-3,5-dimethyl-benzyl)-2-oxo-2-(4-perhydro-1,4-diazepin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(160)

(R)-2-(4-dimethylamino-piperidin-1-yl)-1-(4-methoxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(161)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(162)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(163)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(164)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(165)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(166)

(R)-2-(4,4′-bipiperidinyl-1-yl)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(167)

(R)-2-(1,4′-bipiperidinyl-1′-yl)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(168)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(169)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-2-(4-perhydro-1,4-diazepin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(170)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(171)

(R)-1-(3,5-dibromo-4-methoxy-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(172)

(R)-1-(3,5-dibromo-4-methoxy-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(173)

(R)-1-(3,5-dibromo-4-methoxy-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(174)

(R)-1-(3,5-dibromo-4-methoxy-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(175)

(R)-1-(3,5-dibromo-4-methoxy-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(176)

(R)-2-(4,4′-bipiperidinyl-1-yl)-1-(3,5-dibromo-4-methoxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(177)

(R)-2-(1,4′-bipiperidinyl-1′-yl)-1-(3,5-dibromo-4-methoxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(178)

(R)-1-(3,5-dibromo-4-methoxy-benzyl)-2-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(179)

(R)-1-(3,5-dibromo-4-methoxy-benzyl)-2-oxo-2-(4-perhydro-1,4-diazepin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(180)

(R)-1-(3,5-dibromo-4-methoxy-benzyl)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(181)

(R)-1-(4-amino-3,5-dibromo-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(182)

(R)-1-(4-amino-3,5-dibromo-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(183)

(R)-1-(4-amino-3,5-dibromo-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(184)

(R)-1-(4-amino-3,5-dibromo-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(185)

(R)-1-(4-amino-3,5-dibromo-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(186)

(R)-1-(4-amino-3,5-dibromo-benzyl)-2-(4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(187)

(R)-1-(4-amino-3,5-dibromo-benzyl)-2-(1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(188)

(R)-1-(4-amino-3,5-dibromo-benzyl)-2-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(189)

(R)-1-(4-amino-3,5-dibromo-benzyl)-2-oxo-2-(4-perhydro-1,4-diazepin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(190)

(R)-1-(4-amino-3,5-dibromo-benzyl)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(191)

(R)-1-(4-hydroxy-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(192)

(R)-1-(4-hydroxy-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(193)

(R)-1-(4-hydroxy-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(194)

(R)-1-(4-hydroxy-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(195)

(R)-1-(4-hydroxy-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(196)

(R)-2-(4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(197)

(R)-2-(1,4′-bipiperidinyl-1′-yl)-1-(4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(198)

(R)-1-(4-hydroxy-benzyl)-2-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(199)

(R)-1-(4-hydroxy-benzyl)-2-oxo-2-(4-perhydro-1,4-diazepin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(200)

(R)-2-(4-dimethylamino-piperidin-1-yl)-1-(4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(201)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(202)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(203)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(204)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(205)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(206)

(R)-2-(4,4′-bipiperidinyl-1-yl)-1-(3-bromo-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(207)

(R)-2-(1,4′-bipiperidinyl-1′-yl)-1-(3-bromo-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(208)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(209)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-oxo-2-(4-perhydro-1,4-diazepin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(210)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(211)

(R)-1-(4-amino-3-bromo-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(212)

(R)-1-(4-amino-3-bromo-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(213)

(R)-1-(4-amino-3-bromo-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(214)

(R)-1-(4-amino-3-bromo-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(215)

(R)-1-(4-amino-3-bromo-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(216)

(R)-1-(4-amino-3-bromo-benzyl)-2-(4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tettrahydro-1,3-benzoiazepin-3-yl)-piperidine-1-carboxylate(217)

(R)-1-(4-amino-3-bromo-benzyl)-2-(1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(218)

(R)-1-(4-amino-3-bromo-benzyl)-2-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(219)

(R)-1-(4-amino-3-bromo-benzyl)-2-oxo-2-(4-perhydro-1,4-diazepin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(220)

(R)-1-(4-amino-3-bromo-benzyl)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(221)

(R)-1-(4-amino-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(222)

(R)-1-(4-amino-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(223)

(R)-1-(4-amino-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(224)

(R)-1-(4-amino-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(225)

(R)-1-(4-amino-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(226)

(R)-1-(4-amino-benzyl)-2-(4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(227)

(R)-1-(4-amino-benzyl)-2-(1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(228)

(R)-1-(4-amino-benzyl)-2-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(229)

(R)-1-(4-amino-benzyl)-2-oxo-2-(4-perhydro-1,4-diazepin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(230)

(R)-1-(4-amino-benzyl)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(231)

(R)-1-(4-amino-3,5-dimethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(232)

(R)-1-(4-amino-3,5-dimethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(233)

(R)-1-(4-amino-3,5-dimethyl-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(234)

(R)-1-(4-amino-3,5-dimethyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(235)

(R)-1-(4-amino-3,5-dimethyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(236)

(R)-1-(4-amino-3,5-dimethyl-benzyl)-2-(4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(237)

(R)-1-(4-amino-3,5-dimethyl-benzyl)-2-(1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(238)

(R)-1-(4-amino-3,5-dimethyl-benzyl)-2-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(239)

(R)-1-(4-amino-3,5-dimethyl-benzyl)-2-oxo-2-(4-perhydro-1,4-diazepin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(240)

(R)-1-(4-amino-3,5-dimethyl-benzyl)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(241)

(R)-1-(3,5-bis-trifluoromethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(242)

(R)-1-(3,5-bis-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(243)

(R)-1-(3,5-bis-trifluoromethyl-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(244)

(R)-1-(3,5-bis-trifluoromethyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(245)

(R)-1-(3,5-bis-trifluoromethyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(246)

(R)-2-(4,4′-bipiperidinyl-1-yl)-1-(3,5-bis-trifluoromethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(247)

(R)-2-(1,4′-bipiperidinyl-1′-yl)-1-(3,5-bis-trifluoromethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(248)

(R)-1-(3,5-bis-trifluoromethyl-benzyl)-2-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(249)

(R)-1-(3,5-bis-trifluoromethyl-benzyl)-2-oxo-2-(4-perhydro-1,4-diazepin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(250)

(R)-1-(3,5-bis-trifluoromethyl-benzyl)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(251)

(R)-1-(3-bromo-4-methyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(252)

(R)-1-(3-bromo-4-methyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(253)

(R)-1-(3-bromo-4-methyl-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(254)

(R)-1-(3-bromo-4-methyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(255)

(R)-1-(3-bromo-4-methyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(256)

(R)-2-(4,4′-bipiperidinyl-1-yl)-1-(3-bromo-4-methyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(257)

(R)-2-(1,4′-bipiperidinyl-1′-yl)-1-(3-bromo-4-methyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(258)

(R)-1-(3-bromo-4-methyl-benzyl)-2-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(259)

(R)-1-(3-bromo-4-methyl-benzyl)-2-oxo-2-(4-perhydro-1,4-diazepin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(260)

(R)-1-(3-bromo-4-methyl-benzyl)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(261)

(R)-1-(3-bromo-4-trifluoromethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(262)

(R)-1-(3-bromo-4-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(263)

(R)-1-(3-bromo-4-trifluoromethyl-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(264)

(R)-1-(3-bromo-4-trifluoromethyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(265)

(R)-1-(3-bromo-4-trifluoromethyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(266)

(R)-2-(4,4′-bipiperidinly-1-yl)-1-(3-bromo-4-trifluoromethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(267)

(R)-2-(1,4′-bipiperidinyl-1′-yl)-1-(3-bromo-4-trifluoromethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(268)

(R)-1-(3-bromo-4-trifluoromethyl-benzyl)-2-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(269)

(R)-1-(3-bromo-4-trifluoromethyl-benzyl)-2-oxo-2-(4-perhydro-1,4-diazepin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(270)

(R)-1-(3-bromo-4-trifluoromethyl-benzyl)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(271)

(R)-1-(3-chloro-4-trifluoromethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(272)

(R)-1-(3-chloro-4-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(273)

(R)-1-(3-chloro-4-trifluoromethyl-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(274)

(R)-1-(3-chloro-4-trifluoromethyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(275)

(R)-1-(3-chloro-4-trifluoromethyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(276)

(R)-2-(4,4′-bipiperidinyl-1-yl)-1-(3-chloro-4-trifluoromethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(277)

(R)-2-(1,4′-bipiperidinyl-1′-yl)-1-(3-chloro-4-trifluoromethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(278)

(R)-1-(3-chloro-4-trifluoromethyl-benzyl)-2-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(279)

(R)-1-(3-chloro-4-trifluoromethyl-benzyl)-2-oxo-2-(4-perhydro-1,4-diazepin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(280)

(R)-1-(3-chloro-4-trifluoromethyl-benzyl)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(281)

(R)-1-(3-chloro-4-methyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(282)

(R)-1-(3-chloro-4-methyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(283)

(R)-1-(3-chloro-4-methyl-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(284)

(R)-1-(3-chloro-4-methyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(285)

(R)-1-(3-chloro-4-methyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(286)

(R)-2-(4,4′-bipiperidinyl-1-yl)-1-(3-chloro-4-methyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(287)

(R)-2-(1,4′-bipiperidinyl-1′-yl)-1-(3-chloro-4-methyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(288)

(R)-1-(3-chloro-4-methyl-benzyl)-2-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(289)

(R)-1-(3-chloro-4-methyl-benzyl)-2-oxo-2-(4-perhydro-1,4-diazepin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(290)

(R)-1-(3-chloro-4-methyl-benzyl)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(291)

(R)-1-(4,5-dimethyl-pyridin-2-ylmethyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(292)

(R)-1-(4,5-dimethyl-pyridin-2-ylmethyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(293)

(R)-1-(4,5-dimethyl-pyridin-2-ylmethyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(294)

(R)-1-(4,5-dimethyl-pyridin-2-ylmethyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(295)

(R)-1-(4,5-dimethyl-pyridin-2-ylmethyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(296)

(R)-2-(4,4′-bipiperidinyl-1-yl)-1-(4,5-dimethyl-pyridin-2-ylmethyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(297)

(R)-2-(1,4′-bipiperidinyl-1′-yl)-1-(4,5-dimethyl-pyridin-2-ylmethyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(298)

(R)-1-(4,5-dimethyl-pyridin-2-ylmethyl)-2-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(299)

(R)-1-(4,5-dimethyl-pyridin-2-ylmethyl)-2-oxo-2-(4-perhydro-1,4-diazepin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(300)

(R)-2-(4-dimethylamino-piperidin-1-yl)-1-(4,5-dimethyl-pyridin-2-ylmethyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(301)

(R)-1-(6-amino-5-methyl-pyridin-3-ylmethyl)-2-[4-(1-y-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(302)

(R)-1-(6-amino-5-methyl-pyridin-3-ylmethyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(303)

(R)-1-(6-amino-5-methyl-pyridin-3-ylmethyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(304)

(R)-1-(6-amino-5-methyl-pyridin-3-ylmethyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(305)

(R)-1-(6-amino-5-methyl-pyridin-3-ylmethyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(306)

(R)-1-(6-amino-5-methyl-pyridin-3-ylmethyl)-2-(4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(307)

(R)-1-(6-amino-5-methyl-pyridin-3-ylmethyl)-2-(1,4-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(308)

(R)-1-(6-amino-5-methyl-pyridin-3-ylmethyl)-2-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodi-azepin-3-yl)-piperidine-1-carboxylate(309)

(R)-1-(6-amino-5-methyl-pyridin-3-ylmethyl)-2-oxo-2-(4-perhydro-1,4-diazepin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(310)

(R)-1-(6-amino-5-methyl-pyridin-3-ylmethyl)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(311)

(R)-1-(3,4-dibromo-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidine-1-carboxylate(312)

(R)-1-(3,4-dibromo-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidine-1-carboxylate(313)

(R)-1-(3,4-dibromo-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidine-1-carboxylate (314)

(R)-1-(3,4-dichloro-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidine-1-carboxylate(315)

(R)-1-(3,4-dichloro-benzyl)-2-[4-(1-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidine-1-carboxylate(316)

(R)-1-(3,4-dichloro-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-2,3-dihydro-benzimidazole-1-yl)-piperidine-1-carboxylate (317)

(R)-1-(3,4-dibromo-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-4-phenyl-2,3-dihydro-imidazol-1-yl)-piperidine-1-carboxylate(318)

(R)-1-(3,4-dibromo-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-4-phenyl-2,3-dihydro-imidazol-1-yl)-piperidine-1-carboxylate(319)

(R)-1-(3,4-dibromo-benzyl)-2-(1′-methyl-[4,4′]bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-4-phenyl-2,3-dihydro-imidazol-1-yl)-piperidine-1-carboxylate(320)

(R)-1-(3,4-dichloro-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-4-phenyl-2,3-dihydro-imidazol-1-yl)-piperidine-1-carboxylate(321)

(R)-1-(3,4-dichloro-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-4-phenyl-2,3-dihydro-imidazol-1-yl)-piperidine-1-carboxylate(322)

(R)-1-(3,4-dichloro-benzyl)-2-(1′-methyl-[4,4′]bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-4-phenyl-2,3-dihydro-imidazol-1-yl)-piperidine-1-carboxylate(323)

(R)-1-(3,4-dibromo-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate(324)

(R)-1-(3,4-dibromo-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate(325)

(R)-1-(3,4-dibromo-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate(326)

(R)-1-(3,4-dichloro-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate(327)

(R)-1-(3,4-dichloro-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(5-oxo-3-phenly-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate(328)

(R)-1-(3,4-dichloro-benzyl)-2-[4-(1′-methyl-4,4′-bipiperidinly-1-yl)-2-oxo-ethyl4-(5-oxo-3-phenly-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate(329)

(R)-1-(3,4-dibromo-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-3-dihydro-imidazo[4,5-c]quinolin-3-yl-piperidine-1-carboxylate(330)

(R)-1-(3,4-dibromo-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2-dihydro-imidazo[4,5-c]-quinolin-3-yl-piperidine-1-carboxylate(331)

(R)-1-(3,4-dibromo-benzyl)-2-(1′-(1-methyl-[4,4′]bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl-piperidine-1-carboxylate(332)

(R)-1-(3,4-dichloro-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,3-dihydro-imidazo-[4,5-c]-quinolin-3-yl-piperidine-1-carboxylate(333)

(R)-1-(3,4-dichloro-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2-dihydro-imidazo-[4,5-c]-quinolin-3-yl-piperidine-1-carboxylate(334)

(R)-1-(3,4-dichloro-benzyl)-2-(1′-methyl-[4,4′]bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carboxylate(335)

(R)-1-(3,4-dibromo-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2-dihydro-naphth[1,2-d]-imidazol-3-yl)-piperidine-1-carboxylate(336)

(R)-1-(3,4-dibromo-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2-dihydro-naphth[1,2-d]-imidazol-3-yl)-piperidine-1-carboxylate(337)

(R)-1-(3,4-dibromo-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2-dihydro-naphth[1,2-d]imidazol-3-yl)-piperidine-1-carboxylate(338)

(R)-1-(3,4-dichloro-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2-dihydro-naphth[1,2-d]-imidazol-3-yl)-piperidine-1-carboxylate(339)

(R)-1-(3,4-dichloro-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2-dihydro-naphth[1,2-d]-imidazol-3-yl)-piperidine-1-carboxylate(340)

(R)-1-(3,4-dichloro-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2-dihydro-naphth[1,2-d]imidazol-3-yl)-piperidine-1-carboxylate(341)

(R)-1-(3,4-dibromo-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylate(342)

(R)-1-(3,4-dibromo-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylate(343)

(R)-1-(3,4-dibromo-benzyl)-2-(1′-methyl-[4,4′]bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylate (344)

(R)-1-(3,4-dichloro-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylate(345)

(R)-1-(3,4-dichloro-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylate(346)

(R)-1-(3,4-dichloro-benzyl)-2-(1′-methyl-[4,4′]bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylate (347)

(R)-1-(3,4-dibromo-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(348)

(R)-1-(3,4-dibromo-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(349)

(R)-1-(3,4-dibromo-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(350)

(R)-1-(3,4-dichloro-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(351)

(R)-1-(3,4-dichloro-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(352)

(R)-1-(3,4-dichloro-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(353)

(R)-1-(3,4-dibromo-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,4-dihydro-2H-thieno[3,2-d]-pyrimidin-3-yl)-piperidine-1-carboxylate

No. Structure Name (354)

(R)-1-(3,4-dibromo-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,4-dihydro-2H-thieno[3,2-d]-pyrimidin-3-yl)-piperidine-1-carboxylate(355)

(R)-1-(3,4-dibromo-benzyl)-2-(1′-methyl-[4,4′]bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3-yl)-piperidine-1-carboxylate(356)

(R)-1-(3,4-dichloro-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,4-dihydro-2H-thieno[3,2-d]-pyrimidin-3-yl)-piperidine-1-carboxylate(357)

(R)-1-(3,4-dichloro-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,4-dihydro-2H-thieno[3,2-d]-pyrimidin-3-yl)-piperidine-1-carboxylate(358)

(R)-1-(3,4-dichloro-benzyl)-2-(1′-methyl-[4,4′]bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3-yl)-piperidine-1-carboxylate(359)

(R)-1-(3,4-dibromo-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2-dihydro-4H-thieno[3,4-d]-pyrimidin-3-yl)-piperidine-1-carboxylate(360)

(R)-1-(3,4-dibromo-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2-dihydro-4H-thieno[3,4-d]-pyrimidin-3-yl)-piperidine-1-carboxylate(361)

(R)-1-(3,4-dibromo-benzyl)-2-(1′-methyl-[4,4′]bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2-dihydro-4H-thieno[3,4-d]pyrimidin-3-yl)-piperidine-1-carboxylate(362)

(R)-1-(3,4-dichloro-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2-dihydro-4H-thieno[3,4-d]-pyrimidin-3-yl)-piperidine-1-carboxylate(363)

(R)-1-(3,4-dichloro-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2-dihydro-4H-thieno[3,4-d]-pyrimidin-3-yl)-piperidine-1-carboxylate(364)

(R)-1-(3,4-dichloro-benzyl)-2-(1′-methyl-[4,4′]bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2-dihydro-4H-thieno[3,4-d]pyrimidin-3-yl)-piperidine-1-carboxylate(365)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-(4-morpholin-4-yl-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(366)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-2-[4-(tetrahydro-pyran-4-yl)-piperazin-1-yl]-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(367)

(R)-2-(4-cyclohexyl-piperazin-1-yl)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(368)

(R)-2-(4-cycloheptyl-piperazin-1-yl)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(369)

(R)-2-(4-cyclopentyl-piperazin-1-yl)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(370)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-(4,4-dimethyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(371)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-(4-hydroxy-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(372)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-(4-hydroxy-4-methyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(373)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-(4-ethyl-4-hydroxy-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (374)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-(4-hydroxy-4-trifluormethyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(375)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-[1′-(2-hydroxy-ethyl)-4,4′-bipiperidinyl-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(376)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-{4-[1-(2-hydroxy-ethyl)-piperidin-4-yl]-piperazin-1-yl}-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(377)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-{4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-piperidin-1-yl}-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(378)

(R)-2-(4-amino-4-methyl-1,4′-bipiperidinyl-1′-yl)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(379)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-(4-hydroxy-4-hydroxymethyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(380)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-((R)-3-hydroxy-1,4-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(381)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-((S)-3-hydroxy-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1-benzodiazepin-3-yl)-piperidine-1-carboxylate(382)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-[4-((S)-3-hydroxy-pyrrolidin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(383)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-[4-((R)-3-hydroxy-pyrrolidin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(384)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-(4-hydroxymethyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(385)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-[4-(1-hydroxy-cyclopropyl)-1,4′-bipiperidinyl-1′-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(386)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-(1′-methanesulphonyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(387)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-[4-(4-methanesulphonyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(388)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-[4-(1-methanesulphonyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(389)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-2-(1′-sulphamoyl-4,4′-bipiperidinyl-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(390)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-2-[4-(4-sulphamoyl-piperazin-1-yl)-piperidin-1-yl]-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(391)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-2-[4-(1-sulphamoyl-piperidin-4-yl)-piperazin-1-yl]-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(392)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-(1′-methylsulphamoyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(393)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-[4-(4-methylsulphamoyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(394)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-[4-(1-methylsulphamoyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(395)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-(1′-dimethylsulphamoyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(396)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-[4-(4-dimethylsulphamoyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(397)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-[4-(1-dimethylsulphamoyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(398)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-(1′-ethanesulphonyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(399)

(R)-2-(1′-cyclopropanesulphonyl-4,4′-bipiperidinyl-1-yl)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(400)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-2-[1′-(propan-2-sulphonyl)-4,4′-bipiperidinyl-1-yl]-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(401)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-(4′-hydroxy-1′-methanesulphonyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(402)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-[4-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(403)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-2-{4-[4-(3,3,3-trifluoro-2-oxo-propyl)-piperazin-1-yl]-piperidin-1-yl}-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(404)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(405)

(R)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(406)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-[4-(4-ethoxycarbonylmethyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(407)

(R)-2-[4-(4-carboxymethyl-piperazin-1-yl)-piperidin-1-yl]-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(408)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-[4-(1-ethoxycarbonylmethyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(409)

(R)-2-[4-(1-carboxymethyl-piperidin-4-yl)-piperazin-1-yl]-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(410)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-[1′-(2-ethoxycarbonyl-ethyl)-4,4′-bipiperidinyl-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(411)

(R)-2-[1′-(2-carboxy-ethyl)-4,4′-bipiperidinyl-1-yl]-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(412)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-{4-[1-(2-ethoxycarbonyl-ethyl)-piperidin-4-yl]-piperazin-1-yl}-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(413)

(R)-2-{4-[1-(2-carboxy-ethyl)-piperidin-4-yl]-piperazin-1-yl}-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(414)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-{4-[4-(2-ethoxycarbonyl-ethyl)-piperazin-1-yl]-piperidin-1-yl}-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(415)

(R)-2-{4-[4-(2-carboxy-ethyl)-piperazin-1-yl]-piperidin-1-yl}-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(416)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-[1′-(3-ethoxycarbonyl-propionyl)-4,4′-bipiperidinyl-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(417)

(R)-2-[1′-(3-carboxy-propionyl)-4,4′-bipiperidinyl-1-yl]-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(418)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-{4-[4-(3-ethoxycarbonyl-propionyl)-piperazin-1-yl]-piperidin-1-yl}-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(419)

(R)-2-{4-[4-(3-carboxy-propionyl)-piperazin-1-yl]-piperidin-1-yl}-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(420)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-{4-[1-(3-ethoxycarbonyl-propionyl)-piperidin-4-yl]-piperazin-1-yl}-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(421)

(R)-2-{4-[1-(3-carboxy-propionyl)-piperidin-4-yl]-piperazin-1-yl}-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(422)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-(1′-hydroxycarbamoylmethyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(423)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-{1′-[(hydroxy-methyl-carbamoyl)-methyl]-4,4′-bipiperidinyl-1-yl}-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(424)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-[1′-(methoxycarbamoyl-methyl)-4,4′-bipiperidinyl-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(425)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-[4-(4-hydroxycarbamoylmethyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(426)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-(4-{4-[(hydroxy-methyl-carbamoyl)-methyl]-piperazin-1-yl}-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(427)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-{4-[4-(methoxycarbamoyl-methyl)-piperazin-1-yl]-piperidin-1-yl}-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(428)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-[4-(1-hydroxycarbamoylmethyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(429)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-(4-{1-[(hydroxy-methyl-carbamoyl)-methyl]-piperidin-4-yl}-piperazin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(430)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-{4-[1-(methoxycarbamoyl-methyl)-piperidin-4-yl]-piperazin-1-yl}-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(431)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-(4-ethoxycarbonylmethyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(432)

(R)-2-(4-carboxymethyl-1,4′-bipiperidinyl-1′-yl)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(433)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-[4-(4-ethoxycarbonylmethyl-cyclohexyl)-piperazin-1-yl]-2-oxo-ethylcis-4-(2-oxo-1,2,4,5-tetrahydro-i,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (434)

(R)-2-[4-(4-carboxymethyl-cyclohexyl)-piperazin-1-yl]-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-ethylcis-4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(435)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-[4-(4-ethoxycarbonylmethyl-cyclohexyl)-piperazin-1-yl]-2-oxo-ethyltrans-4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(436)

(R)-2-[4-(4-carboxymethyl-cyclohexyl)-piperazin-1-yl]-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-ethyltrans-4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(437)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-(1′-ethoxyoxalyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(438)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-(1′-oxalyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(439)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-[4-((S)-2-methoxycarbonyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(440)

(R)-2-[4-((S)-2-carboxy-pyrrolidin-1-yl)-piperidin-1-yl]-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(441)

(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-[4-((R)-2-methoxycarbonyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(442)

(R)-2-[4-((R)-2-carboxy-pyrrolidin-1-yl)-piperidin-1-yl]-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(443)

methyl(S)-1′-{(R)-3-(3,5-dibromo-4-hydroxy-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-carbonyloxy]-propionyl}-1,4′-bipiperidinyl-2-carboxylate(444)

(S)-1′-{(R)-3-(3,5-dibromo-4-hydroxy-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-carbonyloxy]-propionyl}-1,4-bipiperidinyl-2-carboxylicacid (445)

methyl(R)-1′-{(R)-3-(3,5-dibromo-4-hydroxy-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-carbonyloxy]-propionyl}-1,4′-bipiperidinyl-2-carboxylate(446)

(R)-1′-{(R)-3-(3,5-dibromo-4-hydroxy-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-carbonyloxy]-propionyl}-1,4-bipiperidinyl-2-carboxylicacid (447)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-(4-morpholin-4-yl-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(448)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-oxo-2-[4-(tetrahydro-pyran-4-yl)-piperazin-1-yl]-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(449)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-(4-cyclohexyl-piperazin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(450)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-(4-cycloheptyl-piperazin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(451)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-(4-cyclopentyl-piperazin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(452)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-(4,4-dimethyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(453)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-(4-hydroxy-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(454)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-(4-hydroxy-4-methyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(455)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-(4-ethyl-4-hydroxy-1,4-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(456)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-(4-hydroxy-4-trifluormethyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(457)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[1′-(2-hydroxy-ethyl)-4,4′-bipiperidinyl-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(458)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-{4-[1-(2-hydroxy-ethyl)-piperidin-4-yl]-piperazin-1-yl}-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(459)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-{4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-piperidin-1-yl}-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(460)

(R)-2-(4-amino-4-methyl-1,4′-bipiperidinyl-1′-yl)-1-(3-bromo-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(461)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-(4-hydroxy-4-hydroxymethyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(462)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-((R)-3-hydroxy-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(463)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-((S)-3-hydroxy-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(464)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[4-((S)-3-hydroxy-pyrrolidin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(465)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[4-((R)-3-hydroxy-pyrrolidin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(466)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-(4-hydroxymethyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(467)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[4-(1-hydroxy-cyclopropyl)-1,4′-bipiperidinyl-1′-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(468)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-(1′-methanesulphonyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(469)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[4-(4-methanesulphonyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(470)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[4-(1-methanesulphonyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(471)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-oxo-2-(1′-sulphamoyl-4,4′-bipiperidinyl-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(472)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-oxo-2-[4-(4-sulphamoyl-piperazin-1-yl)-piperidin-1-yl]-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(473)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-oxo-2-[4-(1-sulphamoyl-piperidin-4-yl)-piperazin-1-yl]-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(474)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-(1′-methylsulphamoyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(475)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[4-(4-methylsulphamoyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(476)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[4-(1-methylsulphamoyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(477)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-(1′-dimethylsulphamoyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(478)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[4-(4-dimethylsulphamoyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(479)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[4-(1-dimethylsulphamoyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(480)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-(1′-ethanesulphonyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(481)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-(1′-cyclopropanesulphonyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(482)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-oxo-2-[1′-(propan-2-sulphonyl)-4,4′-bipiperidinyl-1-yl]-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(483)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-(4′-hydroxy-1′-methanesulphonyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(484)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[4-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(485)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-oxo-2-{4-[4-(3,3,3-trifluoro-2-oxo-propyl)-piperazin-1-yl]-piperidin-1-yl}-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(486)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(487)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(488)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[4-(4-ethoxycarbonylmethyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(489)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[4-(4-carboxymethyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(490)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[4-(1-ethoxycarbonylmethyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(491)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[4-(1-carboxymethyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(492)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[1′-(2-ethoxycarbonyl-ethyl)-4,4′-bipiperidinyl-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(493)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[1′-(2-carboxy-ethyl)-4,4′-bipiperidinyl-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(494)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-{4-[1-(2-ethoxycarbonyl-ethyl)-piperidin-4-yl]-piperazin-1-yl}-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(495)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-{4-[1-(2-carboxy-ethyl)-piperidin-4-yl]-piperazin-1-yl}-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(496)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-{4-[4-(2-ethoxycarbonyl-ethyl)-piperazin-1-yl]-piperidin-1-yl}-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(497)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-{4-[4-(2-carboxy-ethyl)-piperazin-1-yl]-piperidin-1-yl}-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(498)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[1′-(3-ethoxycarbonyl-propionyl)-4,4′-bipiperidinyl-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(499)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[1′-(3-carboxy-propionyl)-4,4′-bipiperidinyl-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(500)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-{4-[4-(3-ethoxycarbonyl-propionyl)-piperazin-1-yl]-piperidin-1-yl}-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(501)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-{4-[4-(3-carboxy-propionyl)-piperazin-1-yl]-piperidin-1-yl}-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(502)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-{4-[1-(3-ethoxycarbonyl-propionyl)-piperidin-4-yl]-piperazin-1-yl}-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(503)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-{4-[1-(3-carboxy-propionyl)-piperidin-4-yl]-piperazin-1-yl}-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(504)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-(1′-hydroxycarbamoylmethyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(505)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-{1′-[(hydroxy-methyl-carbamoyl)-methyl]-4,4′-bipiperidinyl-1-yl}-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(506)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[1′-(methoxycarbamoyl-methyl)-4,4′-bipiperidinyl-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(507)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[4-(4-hydroxycarbamoylmethyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(508)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-(4-{4-[(hydroxy-methyl-carbamoyl)-methyl]-piperazin-1-yl}-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(509)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-{4-[4-(methoxycarbamoyl-methyl)-piperazin-1-yl]-piperidin-1-yl}-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(510)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[4-(1-hydroxycarbamoylmethyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(511)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-(4-{1-[(hydroxy-methyl-carbamoyl)-methyl]-piperidin-4-yl}-piperazin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(512)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-{4-[1-(methoxycarbamoyl-methyl)-piperidin-4-yl]-piperazin-1-yl}-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(513)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-(4-ethoxycarbonylmethyl-1,4-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(514)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-(4-carboxymethyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(515)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[4-(4-ethoxycarbonylmethyl-cyclohexyl)-piperazin-1-yl]-2-oxo-ethyltrans-4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(516)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[4-(4-carboxymethyl-cyclohexyl)-piperazin-1-yl]-2-oxo-ethyltrans-4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(517)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[4-(4-ethoxycarbonylmethyl-cyclohexyl)-piperazin-1-yl]-2-oxo-ethylcis-4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(518)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[4-(4-carboxymethyl-cyclohexyl)-piperazin-1-yl]-2-oxo-ethylcis-4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(519)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-(1′-ethoxyoxalyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(520)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-(1′-oxalyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(521)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[4-((S)-2-methoxycarbonyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(522)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[4-((S)-2-carboxy-pyrrolidin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(523)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[4-((R)-2-methoxycarbonyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(524)

(R)-1-(3-bromo-4-hydroxy-benzyl)-2-[4-((R)-2-carboxy-pyrrolidin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(525)

methyl(S)-1′-{(R)-3-(3-bromo-4-hydroxy-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-carbonyloxy]-propionyl}-1,4′-bipiperidinyl-2-carboxylate(526)

S)-1′-{(R)-3-(3-bromo-4-hydroxy-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-carbonyloxy]-propionyl}-1,4′-bipiperidinyl-2-carboxylicacid (527)

methyl(R)-1′-{(R)-3-(3-bromo-4-hydroxy-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-carbonyloxy]-propionyl}-1,4-bipiperidinyl-2-carboxylate(528)

(R)-1′-{(R)-3-(3-bromo-4-hydroxy-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-carbonyloxy]-propionyl}-1,4-bipiperidinyl-2-carboxylicacid (529)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(4-morpholin-4-yl-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(530)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-[4-(tetrahydro-pyran-4-yl)-piperazin-1-yl]-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(531)

(R)-2-(4-cyclohexyl-piperazin-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(532)

(R)-2-(4-cycloheptyl-piperazin-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(533)

(R)-2-(4-cyclopentyl-piperazin-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(534)

(R)-2-(4,4-dimethyl-1,4′-bipiperidinyl-1′-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(535)

(R)-2-(4-hydroxy-1,4′-bipiperidinyl-1′-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(536)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(4-hydroxy-4-methyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(537)

(R)-2-(4-ethyl-4-hydroxy-1,4-bipiperidinyl-1′-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(538)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(4-hydroxy-4-trifluormethyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(539)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-[1′-(2-hydroxy-ethyl)-4,4′-bipiperidinyl-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(540)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-{4-[1-(2-hydroxy-ethyl)-piperidin-4-yl]-piperazin-1-yl}-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(541)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-{4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-piperidin-1-yl}-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(542)

(R)-2-(4-amino-4-methyl-1,4′-bipiperidinyl-1′-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(543)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(4-hydroxy-4-hydroxymethyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(544)

(R)-2-((R)-3-hydroxy-1,4′-bipiperidinyl-1′-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(545)

(R)-2-((S)-3-hydroxy-1,4′-bipiperidinyl-1′-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(546)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-[4-((S)-3-hydroxy-pyrrolidin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(547)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-[4-((R)-3-hydroxy-pyrrolidin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(548)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(4-hydroxymethyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(549)

(R)-2-[4-(1-hydroxy-cyclopropyl)-1,4′-bipiperidinyl-1′-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(550)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(1′-methanesulphonyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(551)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-[4-(4-methanesulphonyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(552)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-[4-(1-methanesulphonyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(553)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-(1′-sulphamoyl-4,4′-bipiperidinyl-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(554)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-[4-(4-sulphamoyl-piperazin-1-yl)-piperidin-1-yl]-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(555)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-[4-(1-sulphamoyl-piperidin-4-yl)-piperazin-1-yl]-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(556)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(1′-methylsulphamoyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(557)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-[4-(4-methylsulphamoyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(558)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-[4-(1-methylsulphamoyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(559)

(R)-2-(1′-dimethylsulphamoyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(560)

(R)-2-[4-(4-dimethylsulphamoyl-piperazin-1-yl)-piperidin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(561)

4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-(R)-2-[4-(1-dimethyl-sulphamoyl-piperidin-4-yl)-piperazin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl3-yl)-piperidine-1-carboxylate (562)

(R)-2-(1′-ethanesulphonyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(563)

(R)-2-(1′-cyclopropanesulphonyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(564)

4(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-[1′-(propane-2-sulphonyl)-4,4′-bipiperidinyl-1-yl]-ethyl-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(565)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(4′-hydroxy-1′-methanesulphonyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(566)

(R)-2-[4-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-piperidin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(567)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-{4-[4-(3,3,3-trifluoro-2-oxo-propyl)-piperazin-1-yl]-piperidin-1-yl}-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(568)

(R)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(569)

(R)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(570)

(R)-2-[4-(4-ethoxycarbonylmethyl-piperazin-1-yl)-piperidin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(571)

(R)-2-[4-(4-carboxymethyl-piperazin-1-yl)-piperidin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(572)

(R)-2-[4-(1-ethoxycarbonylmethyl-piperidin-4-yl)-piperazin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(573)

(R)-2-[4-(1-carboxymethyl-piperidin-4-yl)-piperazin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(574)

(R)-2-[1′-(2-ethoxycarbonyl-ethyl)-4,4′-bipiperidinyl-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(575)

(R)-2-[1′-(2-carboxy-ethyl)-4,4′-bipiperidinyl-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(576)

(R)-2-{4-[1-(2-ethoxycarbonyl-ethyl)-piperidin-4-yl]-piperazin-1-yl}-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(577)

(R)-2-{4-[1-(2-carboxy-ethyl)-piperidin-4-yl]-piperazin-1-yl}-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(578)

(R)-2-{4-[4-(2-ethoxycarbonyl-ethyl)-piperazin-1-yl]-piperidin-1-yl}-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(579)

(R)-2-{4-[4-(2-carboxy-ethyl)-piperazin-1-yl]-piperidin-1-yl}-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(580)

(R)-2-[1′-(3-ethoxycarbonyl-propionyl)-4,4′-bipiperidinyl-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(581)

(R)-2-[1′-(3-carboxy-propionyl)-4,4′-bipiperidinyl-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(582)

(R)-2-{4-[4-(3-ethoxycarbonyl-propionyl)-piperazin-1-yl]-piperidin-1-yl}-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(583)

(R)-2-{4-[4-(3-carboxy-propionyl)-piperazin-1-yl]-piperidin-1-yl}-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(584)

(R)-2-{4-[1-(3-ethoxycarbonyl-propionyl)-piperidin-4-yl]-piperazin-1-yl}-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(585)

(R)-2-{4-[1-(3-carboxy-propionyl)-piperidin-4-yl]-piperazin-1-yl}-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(586)

(R)-2-(1′-hydroxycarbamoylmethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(587)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-{1′-[(hydroxy-methyl-carbamoyl)-methyl]-4,4′-bipiperidinyl-1-yl}-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(588)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-[1′-(methoxycarbamoyl-methyl)-4,4′-bipiperidinyl-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(589)

(R)-2-[4-(4-hydroxycarbamoylmethyl-piperazin-1-yl)-piperidin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(590)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(4-{4-[(hydroxy-methyl-carbamoyl)-methyl]-piperazin-1-yl}-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(591)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-{4-[4-(methoxycarbamoyl-methyl)-piperazin-1-yl]-piperidin-1-yl}-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(592)

(R)-2-[4-(1-hydroxycarbamoylmethyl-piperidin-4-yl)-piperazin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(593)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(4-{1-[(hydroxy-methyl-carbamoyl)-methyl]-piperidin-4-yl}-piperazin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(594)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-{4-[1-(methoxycarbamoyl-methyl)-piperidin-4-yl]-piperazin-1-yl}-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(595)

(R)-2-(4-ethoxycarbonylmethyl-1,4′-bipiperidinyl-1′-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(596)

(R)-2-(4-carboxymethyl-1,4-bipiperidinyl-1′-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(597)

(R)-2-[4-(4-ethoxycarbonylmethyl-cyclohexyl)-piperazin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyltrans-4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(598)

(R)-2-[4-(4-carboxymethyl-cyclohexyl)-piperazin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyltrans-4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(599)

(R)-2-[4-(4-ethoxycarbonylmethyl-cyclohexyl)-piperazin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethylcis-4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(600)

(R)-2-[4-(4-carboxymethyl-cyclohexyl)-piperazin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethylcis-4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(601)

(R)-2-(1′-ethoxyoxalyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(602)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(1′-oxalyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(603)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-[4-((S)-2-methoxycarbonyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(604)

(R)-2-[4-((S)-2-carboxy-pyrrolidin-1-yl)-piperidin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(605)

(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-[4-((R)-2-methoxycarbonyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(606)

(R)-2-[4-((R)-2-carboxy-pyrrolidin-1-yl)-piperidin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(607)

methyl(S)-1′-{(R)-3-(4-hydroxy-3,5-dimethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-carbonyloxy]-propionyl}-1,4′-bipiperidinyl-2-carboxylate(608)

(S)-1′-{(R)-3-(4-hydroxy-3,5-dimethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-carbonyloxy]-propionyl}-1,4-bipiperidinyl-2-carboxylicacid (609)

methyl(R)-1′-{(R)-3-(4-hydroxy-3,5-dimethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-carbonyloxy]-propionyl}-1,4′-bipiperidinyl-2-carboxylate(610)

(R)-1′-{(R)-3-(4-hydroxy-3,5-dimethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-carbonyloxy]-propionyl}-1,4′-bipiperidinyl-2-carboxylicacid (611)

(R)-1-(3,5-dichloro-4-hydroxy-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(612)

(R)-1-(3,5-dichloro-4-hydroxy-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(613)

(R)-1-(3,5-dichloro-4-hydroxy-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(614)

(R)-1-(3,5-dichloro-4-hydroxy-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(615)

(R)-1-(3,5-dichloro-4-hydroxy-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(616)

(R)-2-(4,4′-bipiperidinyl-1-yl)-1-(3,5-dichloro-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(617)

(R)-2-(1,4′-bipiperidinyl-1′-yl)-1-(3,5-dichloro-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(618)

(R)-1-(3,5-dichloro-4-hydroxy-benzyl)-2-(4-morpholin-4-yl-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(619)

(R)-1-(3,5-dichloro-4-hydroxy-benzyl)-2-oxo-2-[4-(tetrahydro-pyran-4-yl)-piperazin-1-yl]-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(620)

(R)-2-(4-cyclohexyl-piperazin-1-yl)-1-(3,5-dichloro-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(621)

(R)-1-(3,5-dichloro-4-hydroxy-benzyl)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(622)

(R)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-1-(3,5-dichloro-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(623)

(R)-1-(3,5-dichloro-4-hydroxy-benzyl)-2-(4-hydroxy-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(624)

(R)-1-(3,5-dichloro-4-hydroxy-benzyl)-2-(4-hydroxy-4-methyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(625)

(R)-1-(3,5-dichloro-4-hydroxy-benzyl)-2-(4,4-dimethyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(626)

(R)-2-(4-amino-4-methyl-1,4-bipiperidinyl-1′-yl)-1-(3,5-dichloro-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(627)

(R)-1-(3,5-dichloro-4-hydroxy-benzyl)-2-(4-hydroxy-4-hydroxymethyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(628)

(R)-1-(3,5-dichloro-4-hydroxy-benzyl)-2-(1′-methanesulphonyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(629)

(R)-1-(3,5-dichloro-4-hydroxy-benzyl)-2-[4-(4-methane-sulphonyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(630)

(R)-1-(3,5-dichloro-4-hydroxy-benzyl)-2-[4-(1-methane-sulphonyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(631)

(R)-1-(3-chloro-4-hydroxy-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(632)

(R)-1-(3-chloro-4-hydroxy-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(633)

(R)-1-(3-chloro-4-hydroxy-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(634)

(R)-1-(3-chloro-4-hydroxy-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(635)

(R)-1-(3-chloro-4-hydroxy-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(636)

(R)-2-(4,4′-bipiperidinyl-1-yl)-1-(3-chloro-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(637)

(R)-2-(1,4′-bipiperidinyl-1′-yl)-1-(3-chloro-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(638)

(R)-1-(3-chloro-4-hydroxy-benzyl)-2-(4-morpholin-4-yl-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(639)

(R)-1-(3-chloro-4-hydroxy-benzyl)-2-oxo-2-[4-(tetrahydro-pyran-4-yl)-piperazin-1-yl]-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(640)

(R)-1-(3-chloro-4-hydroxy-benzyl)-2-(4-cyclohexyl-piperazin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(641)

(R)-1-(3-chloro-4-hydroxy-benzyl)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(642)

(R)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-1-(3-chloro-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(643)

(R)-1-(3-chloro-4-hydroxy-benzyl)-2-(4-hydroxy-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(644)

(R)-1-(3-chloro-4-hydroxy-benzyl)-2-(4-hydroxy-4-methyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(645)

(R)-1-(3-chloro-4-hydroxy-benzyl)-2-(4,4-dimethyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(646)

(R)-2-(4-amino-4-methyl-1,4′-bipiperidinyl-1′-yl)-1-(3-chloro-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(647)

(R)-1-(3-chloro-4-hydroxy-benzyl)-2-(4-hydroxy-4-hydroxymethyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(648)

(R)-1-(3-chloro-4-hydroxy-benzyl)-2-(1′-methanesulphonyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(649)

(R)-1-(3-chloro-4-hydroxy-benzyl)-2-[4-(4-methanesulphonyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(650)

(R)-1-(3-chloro-4-hydroxy-benzyl)-2-[4-(1-methanesulphonyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(651)

(R)-1-(4-amino-3,5-dimethyl-benzyl)-2-(4-morpholin-4-yl-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(652)

(R)-1-(4-amino-3,5-dimethyl-benzyl)-2-oxo-2-[4-(tetrahydro-pyran-4-yl)-piperazin-1-yl]-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(653)

(R)-1-(4-amino-3,5-dimethyl-benzyl)-2-(4-cyclohexyl-piperazin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(654)

(R)-1-(4-amino-3,5-dimethyl-benzyl)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(655)

(R)-1-(4-amino-3,5-dimethyl-benzyl)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(656)

(R)-1-(4-amino-3,5-dimethyl-benzyl)-2-(4-hydroxy-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(657)

(R)-1-(4-amino-3,5-dimethyl-benzyl)-2-(4-hydroxy-4-methyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(658)

(R)-1-(4-amino-3,5-dimethyl-benzyl)-2-(4,4-dimethyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(659)

(R)-1-(4-amino-3,5-dimethyl-benzyl)-2-(4-amino-4-methyl-1,4-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(660)

(R)-1-(4-amino-3,5-dimethyl-benzyl)-2-(4-hydroxy-4-hydroxymethyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(661)

(R)-1-(4-amino-3,5-dimethyl-benzyl)-2-(1′-methanesulphonyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(662)

(R)-1-(4-amino-3,5-dimethyl-benzyl)-2-[4-(4-methanesulphonyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(663)

(R)-1-(4-amino-3,5-dimethyl-benzyl)-2-[4-(1-methanesulphonyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(664)

(R)-1-(3,5-bis-trifluormethyl-benzyl)-2-(4-morpholin-4-yl-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(665)

(R)-1-(3,5-bis-trifluormethyl-benzyl)-2-oxo-2-[4-(tetrahydro-pyran-4-yl)-piperazin-1-yl]-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(666)

(R)-1-(3,5-bis-trifluormethyl-benzyl)-2-(4-cyclohexyl-piperazin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(667)

(R)-1-(3,5-bis-trifluormethyl-benzyl)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(668)

(R)-1-(3,5-bis-trifluormethyl-benzyl)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(669)

(R)-1-(3,5-bis-trifluormethyl-benzyl)-2-(4-hydroxy-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(670)

(R)-1-(3,5-bis-trifluormethyl-benzyl)-2-(4-hydroxy-4-methyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(671)

(R)-1-(3,5-bis-trifluormethyl-benzyl)-2-(4,4-dimethyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(672)

(R)-2-(4-amino-4-methyl-1,4′-bipiperidinyl-1′-yl)-1-(3,5-bis-trifluormethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(673)

(R)-1-(3,5-bis-trifluormethyl-benzyl)-2-(4-hydroxy-4-hydroxymethyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(674)

(R)-1-(3,5-bis-trifluormethyl-benzyl)-2-(1′-methanesulphonyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(675)

(R)-1-(3,5-bis-trifluormethyl-benzyl)-2-[4-(4-methanesulphonyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(676)

(R)-1-(3,5-bis-trifluormethyl-benzyl)-2-[4-(1-methanesulphonyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(677)

(R)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-1-(3-trifluormethyl-benzyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(678)

(R)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-1-(3-trifluormethyl-benzyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(679)

(R)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-1-(3-trifluormethyl-benzyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(680)

(R)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-1-(3-trifluormethyl-benzyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(681)

(R)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-1-(3-trifluoromethyl-benzyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(682)

(R)-2-(4,4′-bipiperidinyl-1-yl)-2-oxo-1-(3-trifluormethyl-benzyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(683)

(R)-2-(4-hydroxy-1,4′-bipiperidinyl-1′-yl)-2-oxo-1-(3-trifluormethyl-benzyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(684)

(R)-2-(4-hydroxy-4-methyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-1-(3-trifluormethyl-benzyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(685)

(R)-2-(4,4-dimethyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-1-(3-trifluormethyl-benzyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(686)

(R)-2-(4-amino-4-methyl-1,4-bipiperidinyl-1′-yl)-2-oxo-1-(3-trifluormethyl-benzyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazein-3-yl)-piperidine-1-carboxylate(687)

(R)-2-(4-hydroxy-4-hydroxymethyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-1-(3-trifluormethyl-benzyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(688)

(R)-1-(3-methyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(689)

(R)-1-(3-methyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(690)

(R)-1-(3-methyl-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(691)

(R)-1-(3-methyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(692)

(R)-1-(3-methyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(693)

(R)-2-(4,4′-bipiperidinyl-1-yl)-1-(3-methyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(694)

(R)-2-(4-hydroxy-1,4′-bipiperidinyl-1′-yl)-1-(3-methyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(695)

(R)-2-(4-hydroxy-4-methyl-1,4′-bipiperidinyl-1′-yl)-1-(3-methyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(696)

(R)-2-(4,4-dimethyl-1,4′-bipiperidinyl-1′-yl)-1-(3-methyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(697)

(R)-2-(4-amino-4-methyl-1,4′-bipiperidinyl-1′-yl)-1-(3-methyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(698)

(R)-2-(4-hydroxy-4-hydroxymethyl-1,4′-bipiperidinyl-1′-yl)-1-(3-methyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

the enantiomers, the diastereomers and the salts thereof.

The compounds of general formula (I) are prepared by methods known inprinciple. The following methods have proved particularly useful forpreparing the compounds of general formula (I) according to theinvention:

(a) In order to prepare compounds of general formula (I) wherein all thegroups are as hereinbefore defined:

reacting piperidines of general formula

wherein R¹ is as hereinbefore defined,

with carbonic acid derivatives of general formula

wherein Y₁ and Y₂ denote nucleofugic groups, which may be identical ordifferent, preferably the chlorine atom, the p-nitrophenoxy ortrichloromethoxy group, if A denotes the oxygen atom, or the chlorineatom if A denotes the sulphur atom,

and with compounds of general formula

wherein X, D, E, G, M and Q are as hereinbefore defined and Z₁ denotes aprotective group for a carboxy group, for example a C₁₋₆-alkyl or benzylgroup, while the alkyl groups may be straight-chain or branched and thebenzyl group may be substituted by one or two methoxy groups. PreferablyZ₁ denotes the methyl, ethyl, tert-butyl or benzyl group. Before thereaction is carried out any carboxylic acid functions, primary orsecondary amino functions or hydroxy functions present in the group R¹of a compound of formula (III) and/or in a compound of formula (V) maybe protected by conventional protecting groups and any protecting groupsused may be cleaved after the reaction is complete using methodsfamiliar to those skilled in the art.

In a first step the compounds of general formula (III) are reacted withthe carbonic acid derivatives of general formula (IV) in a solvent, forexample in dichloromethane, THF, pyridine or mixtures thereof, at atemperature from −20 to 50° C. in the presence of a base, for exampletriethylamine, pyridine or ethyldiisopropylamine. The resultingintermediate may be purified or further reacted without purification.

The reaction of these intermediates with compounds of general formula(V) also takes place in one of the above-mentioned solvents and at thetemperatures specified above, in the presence of a base, such astriethylamine or pyridine, with or without the addition of an activatingreagent, such as e.g. 4-dimethylaminopyridine. To activate them, thecompounds of general formula (V) may also be deprotonated using a metalhydride, such as e.g. NaH or KH, while in this case there is no need forthe presence of the base of the activating reagent.

(b) In order to prepare compounds of general formula (I) wherein all thegroups are as hereinbefore defined:

coupling a carboxylic acid of general formula

wherein all the groups are as hereinbefore defined, with an amine ofgeneral formula HNR²R³ wherein R² and R³ are as hereinbefore defined.Before the reaction is carried out any carboxylic acid functions,primary or secondary amino functions or hydroxy functions present in acompound of formula (VI) and/or in the groups R² and R³ of the amine offormula HNR²R³ may be protected by conventional protecting groups andany protecting groups used may be cleaved after the reaction is completeusing methods familiar to those skilled in the art.

The coupling is preferably carried out using methods known from peptidechemistry (cf. e.g. Houben-Weyl, Methoden der Organischen Chemie, Vol.15/2), for example using carbodiimides such as e.g.dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide (DIC) orethyl-(3-dimethylaminopropyl)-carbodiimide,O-(1H-benzotriazol-1-yl)-N,N-N′,N′-tetramethyluroniumhexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or1H-benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (BOP).

By adding 1-hydroxybenzotriazole (HOBt) or3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt) the reactionspeed can be increased. The couplings are normally carried out withequimolar amounts of the coupling components as well as the couplingreagent in solvents such as dichloromethane, tetrahydrofuran,acetonitrile, dimethyl formamide (DMF), dimethyl acetamide (DMA),N-methylpyrrolidone (NMP) or mixtures thereof and at temperaturesbetween −30 and +30° C., preferably −20 and +25° C. If necessary,N-ethyl-diisopropylamine (Hünig base) is preferably used as anadditional auxiliary base.

The so-called anhydride process is used as a further coupling method forsynthesising compounds of general formula (I) (cf. also: M. Bodanszky,“Peptide Chemistry”, Springer-Verlag 1988, p. 58-59; M. Bodanszky,“Principles of Peptide Synthesis”, Springer-Verlag 1984, p. 21-27). TheVaughan variant of the mixed anhydride process is preferred (J. R.Vaughan Jr., J. Amer. Chem. Soc. 73, 3547 (1951)), in which the mixedanhydride of the carboxylic acid of general formula (VIII) which is tobe coupled and monoisobutyl carbonate is obtained, using isobutylchlorocarbonate in the presence of bases such as 4-methylmorpholine or4-ethylmorpholine. The preparation of this mixed anhydride and thecoupling with the amines of general formula HNR²R³ are carried out in aone-pot process, using the above-mentioned solvents and at temperaturesbetween −20 and +25° C., preferably 0° C. and +25° C.

(c) In order to prepare compounds of general formula (I) wherein all thegroups are as hereinbefore defined:

coupling a compound of general formula

with an amine of general formula HNR²R³,

wherein all the groups are as hereinbefore defined and Nu denotes aleaving group, for example a halogen atom, such as the chlorine, bromineor iodine atom, an alkylsulphonyloxy group with 1 to 10 carbon atoms inthe alkyl moiety, a phenylsulphonyloxy or naphthylsulphonyloxy groupoptionally mono-, di- or trisubstituted by chlorine or bromine atoms orby methyl or nitro groups, while the substituents may be identical ordifferent, a 1H-imidazol-1-yl, a 1H-pyrazol-1-yl optionally substitutedby one or two methyl groups in the carbon skeleton, a1H-1,2,4-triazol-1-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3,4-tetrazol-1-yl,a vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl,pentachlorophenyl, pentafluorophenyl, pyranyl or pyridinyl, adimethylaminyloxy, 2(1H)-oxopyridin-1-yl-oxy,2,5-dioxopyrrolidin-1-yloxy, phthalimidyloxy, 1H-benzo-triazol-1-yloxyor azide group. Before the reaction is carried out any carboxylic acidfunctions, primary or secondary amino functions or hydroxy functionspresent in a compound of formula (VII) and/or in the groups R² and R³ ofthe amine of formula HNR²R³ may be protected by conventional protectinggroups and any protecting groups used may be cleaved after the reactionis complete using methods familiar to those skilled in the art.

The reaction is carried out under Schotten-Baumann or Einhornconditions, i.e. the components are reacted in the presence of at leastone equivalent of an auxiliary base at temperatures between −50° C. and+120° C., preferably −10° C. and +30° C., and optionally in the presenceof solvents. The auxiliary bases used are preferably alkali metal andalkaline earth metal hydroxides, e.g. sodium hydroxide, potassiumhydroxide or barium hydroxide, alkali metal carbonates, e.g. sodiumcarbonate, potassium carbonate or caesium carbonate, alkali metalacetates, e.g. sodium or potassium acetate, as well as tertiary amines,e.g. pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine,N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine,1,4-diazabicyclo[2,2,2]octane or 1,8-diazabicyclo[5,4,0]undec-7-ene, thesolvents used may be, for example, dichloromethane, tetrahydrofuran,1,4-dioxane, acetonitrile, dimethyl formamide, dimethyl acetamide,N-methyl-pyrrolidone or mixtures thereof; if alkali metal or alkalineearth metal hydroxides, alkali metal carbonates or acetates are used asthe auxiliary bases, water may also be added to the reaction mixture ascosolvent.

The new compounds of general formula (I) according to the inventioncontain one or more chiral centres. If for example there are two chiralcentres the compounds may occur in the form of two pairs ofdiastereomeric antipodes. The invention covers the individual isomers aswell as the mixtures thereof.

The diastereomers may be separated on the basis of their differentphysico-chemical properties, e.g. by fractional crystallisation fromsuitable solvents, by high pressure liquid or column chromatography,using chiral or preferably non-chiral stationary phases.

Racemates covered by general formula (I) may be separated for example byHPLC on suitable chiral stationary phases (e.g. Chiral AGP, ChiralpakAD). Racemates which contain a basic or acidic function can also beseparated via the diastereomeric, optically active salts which areproduced on reacting with an optically active acid, for example (+) or(−)-tartaric acid, (+) or (−)-diacetyl tartaric acid, (+) or(−)-monomethyl tartrate or (+)-cam-phorsulphonic acid, or an opticallyactive base, for example with (R)-(+)-1-phenylethylamine,(S)-(−)-1-phenylethylamine or (S)-brucine.

According to a conventional method of separating isomers, the racemateof a compound of general formula (I) is reacted with one of theabove-mentioned optically active acids or bases in equimolar amounts ina solvent and the resulting crystalline, diastereomeric, opticallyactive salts thereof are separated using their different solubilities.This reaction may be carried out in any type of solvent provided that itis sufficiently different in terms of the solubility of the salts.Preferably, methanol, ethanol or mixtures thereof, for example in aratio by volume of 50:50, are used. Then each of the optically activesalts is dissolved in water, carefully neutralised with a base such assodium carbonate or potassium carbonate, or with a suitable acid, e.g.dilute hydrochloric acid or aqueous methanesulphonic acid, and in thisway the corresponding free compound is obtained in the (+) or (−) form.

The (R) or (S) enantiomer alone or a mixture of two optically activediastereomeric compounds covered by general formula I may also beobtained by performing the syntheses described above with a suitablereaction component in the (R) or (S) configuration.

If the group X in compounds of general formula (V) denotes the oxygenatom, the hydroxycarboxylic acids of general formula

needed for the synthesis may be obtained from compounds of generalformula

wherein D, E, G, M and Q in both formulae are as hereinbefore defined.

By diazotising compounds of general formula (IX) with a suitablediazotising reagent, preferably sodium nitrite in an acid medium, it ispossible to obtain the compounds of general formula (VIII). Ifenantiomerically pure compounds are used the correspondingenantiomerically pure hydroxycarboxylic acid compounds are obtained, theconfiguration being retained as the reaction proceeds.

An alternative method of obtaining compounds of general formula (VIII)comprises reacting aldehydes of general formula (X) with N-acetylglycinein acetic anhydride as solvent in the presence of alkali metal acetate,preferably sodium or potassium acetate at suitable temperature,preferably at 80-130° C.

The azlactones formed as primary products are hydrolysed without beingisolated to form the compounds of general formula (XI).

By further reaction in the presence of aqueous inorganic acids such assulphuric, phosphoric or hydrochloric acid, but preferably hydrochloricacid, compounds of general formula (XII) are obtained. These are thenconverted with suitable reducing agents into the compounds of generalformula (VIII).

The reducing agents used may be alkali metal borohydrides, such assodium or potassium borohydride. Other reducing agents arechlorodialkylboranes, such as chlorodicyclohexylborane. If chiralchlorodialkylboranes are used, such as e.g.B-chlorodiisopinocampheylborane, the compounds of general formula (VIII)may be isolated in enantiomerically pure form.

Another way of obtaining compounds of general formula (VIII) comprisesalkylating the compound (XIII)

with aryl- or heteroaryl-methylhalides of general formula

wherein Hal denotes a chlorine, bromine or iodine atom, and D, E, G, Qand E are as hereinbefore defined, analogously to methods known from theliterature (Michael T. Crimmins, Kyle A. Emmitte and Jason D. Katz, Org.Lett. 2, 2165-2167 [2000]). The diastereomeric products formed may thenbe separated using physicochemical methods, preferably usingchromatographic methods or recrystallisation. The hydrolytic cleaving ofthe chiral auxiliary and cleaving of the benzyl protecting group alsoopen up a possible method of obtaining enantiomerically purehydroxycarboxylic acid compounds of general formula (V).

The further reaction of compounds of general formula (VIII) to obtaincompounds of general formula (V) is carried out in the alcoholic medium,preferably in methanol or ethanol, in the presence of a suitable acid,such as hydrochloric acid. The reaction may alternatively be carried outby reacting with thionyl chloride in alcoholic solvents, preferablymethanol.

If the group X in compounds of general formula (V) denotes the sulphuratom, the thiocarboxylic acids of general formula

needed for the synthesis, wherein D, E, G, M and Q are as hereinbeforedefined and Z₁ denotes a protective group for a carboxy group asdescribed under process (a), may be obtained from compounds of generalformula (V) wherein X denotes the oxygen atom.

By Mitsunobu reaction of the compounds of general formula (V) withC₁₋₆-alkylthiocarboxylic acids, where the alkyl chain may be straight orbranched but preferably denotes the methyl group, the correspondingalkylthiocarboxylic acid esters of these compounds are obtained. Thesemay be hydrolysed according to known methods to obtain the compounds ofgeneral formula (XV) (Bert Strijtveen and Richard M. Kellogg, J. Org.Chem. 51, 3664-3671 [1986]).

All compounds of general formula (I) which contain primary or secondaryamino, hydroxy or hydroxycarbonyl functions are preferably obtained fromprecursors comprising protective groups. Examples of protective groupsfor amino functions include for example a benzyloxycarbonyl,2-nitrobenzyloxycarbonyl, 4-nitro-benzyloxycarbonyl,4-methoxy-benzyloxycarbonyl, 2-chloro-benzyloxycarbonyl,3-chloro-benzyloxycarbonyl, 4-chloro-benzyloxycarbonyl,4-biphenylyl-α,α-dimethyl-benzyloxycarbonyl or3,5-dimethoxy-α,α-dimethyl-benzyloxycarbonyl group, an alkoxycarbonylgroup with a total of 1 to 5 carbon atoms in the alkyl moiety, forexample the methoxycarbonyl, ethoxy-carbonyl, n-propoxycarbonyl,isopropoxycarbonyl, n-butoxycarbonyl, 1-methylpro-poxycarbonyl,2-methylpropoxy-carbonyl or tert-butyloxycarbonyl group whichallyloxycarbonyl, 2,2,2-trichloro-(1,1-dimethylethoxy)carbonyl or9-fluorenyl-methoxycarbonyl group or a formyl, acetyl or trifluoroacetylgroup.

The protective group for hydroxy functions may be, for example, atrimethylsilyl, triethylsilyl, triisopropyl, tert-butyldimethylsilyl ortert-butyldiphenylsilyl group, a tert-butyl, benzyl, 4-methoxybenzyl or3,4-dimethoxybenzyl group.

The protective group for hydroxycarbonyl functions may be for example analkyl group with a total of 1 to 5 carbon atoms, for example the methyl,ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, allyl,2,2,2-trichloroethyl, benzyl or 4-methoxybenzyl group.

The compounds of general formula I obtained may, if they containsuitable basic functions, be converted, particularly for pharmaceuticaluse, into their physiologically acceptable salts with inorganic ororganic acids. Suitable acids include for example hydrochloric acid,hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid,methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid,p-toluenesulphonic acid, acetic acid, fumaric acid, succinic acid,lactic acid, mandelic acid, malic acid, citric acid, tartaric acid ormaleic acid.

Moreover, the new compounds of formula (I), if they contain a carboxylicacid function, may be converted into the addition salts thereof withinorganic or organic bases, particularly for pharmaceutical use into thephysiologically acceptable addition salts thereof. Suitable bases forthis include, for example, sodium hydroxide, potassium hydroxide,ammonia, cyclohexylamine, dicyclohexylamine, ethanolamine,diethanolamine and triethanolamine.

The present invention relates to racemates if the compounds of generalformula (I) have only one chiral element. However, the application alsoincludes the individual diastereomeric pairs of antipodes or mixturesthereof which are obtained if there is more than one chiral element inthe compounds of general formula (I), as well as the individualoptically active enantiomers of which the above-mentioned racemates aremade up.

Also included in the subject matter of this invention are the compoundsaccording to the invention, including the salts thereof, in which one ormore hydrogen atoms, for example one, two, three, four or five hydrogenatoms, are replaced by deuterium.

The new compounds of general formula (I) and the physiologicallyacceptable salts thereof have valuable pharmacological properties, basedon their selective CGRP-antagonistic properties. The invention furtherrelates to pharmaceutical compositions containing these compounds, theiruse and the preparation thereof.

The new compounds of general formula I mentioned above and thephysiologically acceptable salts thereof have CGRP-antagonisticproperties and exhibit good affinities in CGRP receptor binding studies.The compounds display CGRP-antagonistic properties in thepharmacological test systems described hereinafter.

The following experiments were carried out to demonstrate the affinityof the above-mentioned compounds for human CGRP-receptors and theirantagonistic properties:

A. Binding Studies with SK-N-MC Cells (Expressing the Human CGRPReceptor)

SK-N-MC cells are cultivated in “Dulbecco's modified Eagle medium”. Themedium is removed from confluent cultures. The cells are washed twicewith PBS buffer (Gibco 041-04190 M), detached by the addition of PBSbuffer mixed with 0.02% EDTA, and isolated by centrifuging. Afterresuspension in 20 ml of “Balanced Salts Solution” [BSS (in mM): NaCl120, KCl 5.4, NaHCO₃ 16.2, MgSO₄ 0.8, NaHPO₄ 1.0, CaCl₂ 1.8, D-glucose5.5, HEPES 30, pH 7.40] the cells are centrifuged twice at 100×g andresuspended in BSS. After the number of cells has been determined, thecells are homogenised using an Ultra-Turrax and centrifuged for 10minutes at 3000×g. The supernatant is discarded and the pellet isrecentrifuged in Tris buffer (10 mM Tris, 50 mM NaCl, 5 mM MgCl₂, 1 mMEDTA, pH 7.40) enriched with 1% bovine serum albumin and 0.1%bacitracin, and resuspended (1 ml/1000000 cells). The homogenisedproduct is frozen at −80° C. The membrane preparations are stable formore than 6 weeks under these conditions.

After thawing, the homogenised product is diluted 1:10 with assay buffer(50 mM Tris, 150 mM NaCl, 5 mM MgCl₂, 1 mM EDTA, pH 7.40) andhomogenised for 30 seconds with an Ultra-Turrax. 230 μl of thehomogenised product are incubated for 180 minutes at ambient temperaturewith 50 pM ¹²⁵I-iodotyrosyl-Calcitonin-Gene-Related Peptide (Amersham)and increasing concentrations of the test substances in a total volumeof 250 μl. The incubation is ended by rapid filtration throughGF/B-glass fibre filters treated with polyethyleneimine (0.1%) using acell harvester. The protein-bound radioactivity is measured using agamma counter. Non-specific binding is defined as the boundradioactivity in the presence of 1 μM human CGRP-alpha duringincubation.

The concentration binding curves are analysed using computer-aidednon-linear curve matching.

The compounds mentioned hereinbefore show IC₅₀ values ≦10000 nM in thetest described.

B. CGRP Antagonism in SK-N-MC Cells

SK-N-MC cells (1 million cells) are washed twice with 250 μl incubationbuffer (Hanks' HEPES, 1 mM 3-isobutyl-1-methylxanthine, 1% BSA, pH 7.4)and pre-incubated at 37° C. for 15 minutes. After the addition of CGRP(10 μl) as agonist in increasing concentrations (10⁻¹¹ to 10⁻⁶ M), oradditionally the substance in 3 to 4 different concentrations, themixture is incubated for another 15 minutes.

Intracellular cAMP is then extracted by the addition of 20 μl of 1M HCland centrifugation (2000×g, 4° C., for 15 minutes). The supernatants arefrozen in liquid nitrogen and stored at −20° C.

The cAMP contents of the samples are determined by radioimmunoassay(Messrs. Amersham) and the pA₂ values of antagonistically actingsubstances are determined graphically.

The compounds of general formula I exhibit CGRP-antagonistic propertiesin the in vitro test model described, in a dosage range between 10⁻¹²and 10⁻⁵ M.

In view of their pharmacological properties the compounds of generalformula I and the salts thereof with physiologically acceptable acidsare thus suitable for the acute and prophylactic treatment of headaches,particularly migraine or cluster headaches. Moreover, the compounds ofgeneral formula I also have a positive effect on the following diseases:non-insulin-dependent diabetes mellitus (“NIDDM”), complex regional painsyndrome (CRPS1), cardiovascular diseases, morphine tolerance, diarrhoeacaused by clostridium toxin, skin diseases, particularly thermal andradiation-induced skin damage including sunburn, inflammatory diseases,e.g. inflammatory diseases of the joints (arthritis), neurogenicinflammation of the oral mucosa, inflammatory lung diseases, allergicrhinitis, asthma, diseases accompanied by excessive vasodilatation andresultant reduced blood supply to the tissues, e.g. shock and sepsis. Inaddition, the compounds according to the invention have a generalpain-relieving effect.

The symptoms of menopausal hot flushes caused by vasodilatation andincreased blood flow in oestrogen-deficient women and hormone-treatedpatients with prostate carcinoma are favourably affected by theCGRP-antagonists of the present application in a preventive andacute-therapeutic capacity, this therapeutic approach beingdistinguished from hormone replacement by the absence of side effects.

The dosage required to achieve a corresponding effect is conveniently0.0001 to 3 mg/kg of body weight, preferably 0.01 to 1 mg/kg of bodyweight, when administered intravenously or subcutaneously and 0.01 to 10mg/kg of body weight, preferably 0.1 to 10 mg/kg of body weight whenadministered orally, nasally or by inhalation, 1 to 3× a day in eachcase.

If the treatment with CGRP antagonists and/or CGRP release inhibitors isgiven as a supplement to conventional hormone substitution, it isadvisable to reduce the doses specified above, in which case the dosagemay be from ⅕ of the lower limits mentioned above up to 1/1 of the upperlimits specified.

The compounds prepared according to the invention may be administeredeither on their own or optionally in combination with other activesubstances for the treatment of migraine by intravenous, subcutaneous,intramuscular, intrarectal, intranasal route, by inhalation,transdermally or orally, while aerosol formulations are particularlysuitable for inhalation. The combinations may be administered eithersimultaneously or sequentially.

Categories of active substance which may be used in the combinationinclude e.g. antiemetics, prokinetics, neuroleptics, antidepressants,neurokinine antagonists, angiotensin receptor blockers (angiotensin IIantagonists), iNOS inhibitors, AMPA antagonists, anticonvulsants,histamine-H1 receptor antagonists, antimuscarinics, β-blockers,α-agonists and α-antagonists, ergot alkaloids, mild analgesics,non-steroidal antiinflammatories, corticosteroids, calcium antagonists,5-HT_(1B/1D) agonists or other anti-migraine agents, which may beformulated together with one or more inert conventional carriers and/ordiluents, e.g. with corn starch, lactose, glucose, microcrystallinecellulose, magnesium stearate, polyvinyl pyrrolidone, citric acid,tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol,water/polyethylene glycol, propylene glycol, cetylstearyl alcohol,carboxymethylcellulose or fatty substances such as hard fat or suitablemixtures thereof, into conventional galenic preparations such as plainor coated tablets, capsules, powders, suspensions, solutions, metereddose aerosols or suppositories.

Thus other active substances which may be used for the combinationsmentioned above include for example the non-steroidal antiinflammatoriesaceclofenac, acemetacin, acetyl-salicylic acid, azathioprine,diclofenac, diflunisal, fenbufen, fenoprofen, flurbiprofen, ibuprofen,indometacin, ketoprofen, leflunomide, lornoxicam, mefenamic acid,naproxen, phenylbutazone, piroxicam, sulphasalazine, zomepirac or thepharmaceutically acceptable salts thereof as well as meloxicam and otherselective COX2-inhibitors, such as for example rofecoxib and celecoxib.

It is also possible to use ergotamine, dihydroergotamine,metoclopramide, domperidone, diphenhydramine, cyclizine, promethazine,chlorpromazine, vigabatrin, timolol, isometheptene, pizotifen, botox,gabapentin, topiramate, riboflavin, montelukast, lisinopril,prochloroperazine, dexamethasone, flunarizine, dextropropoxyphene,meperidine, metoprolol, propranolol, nadolol, atenolol, clonidine,indoramin, carbamazepine, phenytoin, valproate, amitryptiline, lidocaineor diltiazem and other 5-HT_(1B/1D)-agonists such as, for example,almotriptan, avitriptan, eletriptan, frovatriptan, naratriptan,rizatriptan, sumatriptan and zolmitriptan.

The dosage of these active substances is expediently ⅕ of the lowestrecommended dose to 1/1 of the normally recommended dose, i.e. forexample 20 to 100 mg of sumatriptan.

The invention further relates to the use of the compounds according tothe invention as valuable adjuvants for the production and purification(by affinity chromatography) of antibodies as well as in RIA and ELISAassays, after suitable radioactive labelling, for example by tritiationof suitable precursors, for example by catalytic hydrogenation withtritium or replacing halogen atoms with tritium, and as a diagnostic oranalytical adjuvant in neurotransmitter research.

EXPERIMENTAL SECTION

As a rule, IR, ¹H-NMR and/or mass spectra have been obtained for thecompounds prepared.

Unless otherwise stated, R_(f) values are obtained using ready-madesilica gel TLC plates 60 F254 (E. Merck, Darmstadt, Item no. 1.05714)without chamber saturation.

The R_(f) values obtained under the name Polygram are obtained usingready-made Polygram SIL G/UV₂₅₄ TLC films (coated with 0.2 mm silicagel) made by Messrs Macherey-Nagel (Düren, Item no. 805 021).

The R_(f) values obtained under the name Polygram-Alox are obtainedusing ready-made Polygram Alox N/UV₂₅₄ TLC plates (coated with 0.2 mmaluminium oxide) made by Messrs Macherey-Nagel (Düren, Item no. 802021).

The ratios given for the eluants relate to units by volume of thesolvent in question. The units by volume specified for NH₃ refer to aconcentrated solution of NH₃ in water.

Unless otherwise stated, the acid, base and salt solutions used forworking up the reaction solutions are aqueous systems of theconcentrations specified.

For chromatographic purification, silica gel made by Millipore (MATREX™,35-70 μm) is used.

For chromatographic purification, aluminium oxide made by Messrs ICNBiomedicals (Eschwege, Item no. 02090) is used. The required activitystage is produced before use in accordance with the manufacturer'sinstructions.

The HPLC data provided are measured using the parameters specifiedbelow:

Method A:

percent by volume of water percent by volume of acetonitrile time (min)(with 0.1% formic acid) (with 0.1% formic acid) 0 95 5 9 10 90 10 10 9011 95 5

Analytical column: Zorbax column (Agilent Technologies), SB (StableBond) C18; 3.5 μm; 4.6×75 mm; column temperature: 30° C.; flow: 0.8mL/min; injection volume: 5 μL; detection at 254 nm

Method B:

percent by volume of water percent by volume of acetonitrile time (min)(with 0.1% formic acid) (with 0.1% formic acid) 0 95 5 9 10 90 10 10 9011 95 5

Analytical column: Waters Symmetry C18; 3.5 μm; 4.6×75 mm; columntemperature: 30° C.; 0.8 mL/min; injection volume: 5 μL; detection at254 nm

Method C:

percent by volume of water percent by volume of acetonitrile time (min)(with 0.1% formic acid) (with 0.1% formic acid) 0 95 5 8 50 50 9 10 9010 10 90 11 90 10

Analytical column: Zorbax column (Agilent Technologies), Bonus-RP C14;3.5 μm; 4.6×75 mm; column temperature: 30° C.; flow: 0.8 mL/min;injection volume: 5 μL; detection at 254 nm

Method D:

percent by volume of water percent by volume of acetonitrile time (min)(with 0.1% formic acid) (with 0.1% formic acid) 0 95 5 8 50 50 9 10 9010 10 90 11 90 10

Analytical column: Zorbax-column (Agilent Technologies), SB (StableBond) C18; 3.5 μm; 4.6×75 mm; column temperature: 30° C.; flow: 0.8mL/min; injection volume: 5 μL; detection at 254 nm

Method E:

percent by volume of water percent by volume of acetonitrile time (min)(with 0.1% formic acid) (with 0.1% formic acid) 0 95 5 4.5 10 90 5 10 905.5 90 10

Analytical column: Zorbax column (Agilent Technologies), SB (StableBond) C18; 3.5 μm; 4.6×75 mm; column temperature: 30° C.; flow: 1.6mL/min; injection volume: 5 μL; detection at 254 nm

Method F:

time percent by volume of water percent by volume of acetonitrile (min)(with 0.04% trifluoroacetic acid) (with 0.04% trifluoroacetic acid) 0 8020 30 20 80

Analytical column: Waters Symmetry C8; 5 μm; 4.6×150 mm; columntemperature: 25° C.; flow: 1.3 mL/min; injection volume: 5 μL; detectionat 254 nm

In preparative HPLC purifications as a rule the same gradients are usedas were used to collect the analytical HPLC data.

The products are collected under mass control and the fractionscontaining the product are combined and freeze-dried.

If no detailed information is given as to the configuration, it is notclear whether it is a pure enantiomer or whether partial or evencomplete racemisation has occurred.

The following abbreviations are used in the description of theexperiments:

Boc tert-butoxycarbonyl cyc cyclohexane DCM dichloromethane DIPEdiisopropylether DMF N,N-dimethylformamide EtOAc ethyl acetate EtOHethanol Fmoc 9-fluorenylmethoxycarbonyl semiconc. semi-concentrated HATUO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetra-methyluronium-hexafluorophosphate HCl hydrochloric acid HOAc acetic acidHOBt 1-hydroxybenzotriazole-hydrate i. vac. in vacuo (under vacuum) KOHpotassium hydroxide conc. concentrated LiOH lithium hydroxide MeOHmethanol NaOAc sodium acetate NaCl sodium chloride NaOH sodium hydroxiden.d. not determined PE petroleum ether RT ambient temperature TBMEtert-butylmethylether TBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetra-methyluronium-tetrafluoroborate TFA trifluoroacetic acid THFtetrahydrofuran

Example 1(R)-1-(3,4-dibromo-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

1a (Z,E)-2-acetylamino-3-(3,4-dibromo-phenyl)-acrylic acid

A mixture of 22.1 g (83.7 mmol) of 3,4-dibromobenzaldehyde, 14.7 g (126mmol) N-acetylglycine and 10.3 g (126 mmol) NaOAc in 100 mL aceticanhydride was heated to 118° C. (internal temperature) for 1.5 h. Afterthe reaction had ended the reaction mixture was cooled to 100° C andthen combined batchwise with 20 g ice (exothermic reaction), while theinternal temperature was kept below 120° C. The reaction mixture washeated to 95° C. for a further 2 h, then added to a mixture of 240 mLwater and 120 mL toluene and stirred for 1 h at RT. The precipitate wassuction filtered, washed with 50 mL each of toluene and water and driedovernight at 40° C. in the circulating air dryer.

Yield: 20.8 g (69% of theory)

ESI-MS: (M+H)⁺=362/364/366 (2 Br)

R_(f)=0.19 (silica gel, EtOAc/MeOH/NH₃ 90:10:1)

1b 3-(3,4-dibromo-phenyl)-2-oxo-propionic acid

125 mL ice-cooled 4 M HCl were added to a solution of 11.98 g (32.82mmol) (Z,E)-2-acetylamino-3-(3,4-dibromo-phenyl)-acrylic acid in 90 mLN-methyl-2-pyrrolidinone and the reaction mixture was then refluxed for2 h. The reaction solution cooled to approx. 40° C. was poured onto 450mL water, the suspension formed was combined with 300 mL toluene andstirred overnight. The organic phase was extracted with water until aprecipitate formed between the phases. This was suction filtered, thephases were separated, the toluene phase was evaporated down by half,mixed with water again and the precipitate formed was suction filtered.It was then combined with the first precipitate and dried at 50° C. inthe circulating air dryer.

Yield: 5.73 g (54% of theory)

ESI-MS: (M+H)⁺=319/321/323 (2 Br)

R_(f)=0.17 (silica gel, EtOAc/MeOH/NH₃ 80:20:2)

1c (R)-3-(3,4-dibromo-phenyl)-2-hydroxy-propionic acid

A solution of 6.1 g (19.0 mmol) (1R)-B-chlorodiisopinocampheylborane in40 mL THF was added dropwise within 30 min to a solution of 5.1 g (15.8mmol) 3-(3,4-dibromo-phenyl)-2-oxo-propionic acid and 2.2 mL (15.8 mmol)triethylamine in 20 mL THF which had been cooled to −35° C. and thereaction mixture was kept at this temperature for 1 h. The reactionsolution was carefully combined with 30 mL 1 M NaOH (exothermic) and 30mL tert-butylmethylether, stirred for 15 min, the organic phase wasseparated off, then extracted with 25 mL water and 15 mL 1 M NaOH. Thecombined aqueous phases were acidified with 2 M HCl, extracted threetimes with in each case 40 mL tert-butylmethylether and the combinedorganic phases were dried over Na₂SO₄. After the desiccant and solventhad been eliminated the residue was purified by chromatography (silicagel, EtOAc/MeOH/NH₃ 70:30:3).

Yield: 3.2 g (63% of theory)

ESI-MS: (M+H)⁺=321/323/325 (2 Br)

retention time (HPLC): 7.0 min (method A)

1d ethyl (R)-3-(3,4-dibromo-phenyl)-2-hydroxy-propionate

0.8 mL (10.9 mmol) thionyl chloride were added dropwise to a solution of3.2 g (9.9 mmol) of (R)-3-(3,4-dibromo-phenyl)-2-hydroxy-propionic acidin 40 mL dry EtOH cooled to 0° C. and the reaction mixture was stirredfor 1 h at RT. The reaction solution was evaporated down i.vac. theresidue combined with 30 mL DCM and filtered to remove the insolubleprecipitate. After the solvent had been eliminated the product wasobtained as a viscous oil, which was further reacted withoutpurification.

Yield: 3.1 g (88% of theory)

ESI-MS: (M+H)⁺=351/353/355 (2 Br)

retention time (HPLC): 8.1 min (method A)

1e4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonylchloride

6 g (12.1 mmol) phosgene (20 percent by weight in toluene) were added toa solution of 2.5 g (10.2 mmol)3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 2.6 mL(14.9 mmol) ethyldiisopropylamine in 75 mL DCM cooled to 0° C. and thereaction mixture was stirred for 30 min at this temperature. The mixturewas allowed to warm up to RT, evaporated down i.vac. to approx. 50 mLand filtered through silica gel, this was washed with 200 mL DCM/EtOAc(1:1) and the combined organic filtrates were again evaporated downi.vac. The residue was stirred with DIPE, suction filtered and driedi.vac.

Yield: 2.42 g (77% of theory)

R_(f)=0.43 (silica gel, DCM/EtOAc 1:1)

1f (R)-2-(3,4-dibromo-phenyl)-1-ethoxycarbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

362 mg (55% in mineral oil, 9.06 mmol) NaH were added batchwise to asolution of 2.90 g (8.24 mmol) of(R)-3-(3,4-dibromo-phenyl)-2-hydroxy-propionate ethyl in 50 mL dry THFcooled to 0° C. and the mixture was stirred for a further 30 min at thistemperature, during which time a dark brown suspension formed.Subsequently 2.15 g (6.99 mmol)4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonylchloridewere added batchwise while being cooled and the reaction mixture wasstirred for 2 h at RT. 50 mL of semisaturated NaHCO₃ solution wereadded, the mixture was extracted twice with in each case 50 mL EtOAc,the combined organic phases were washed with 50 mL saturated NaClsolution and the organic phase was filtered through Na₂SO₄. After thesolvent has been eliminated the residue was purified by chromatography(silica gel, EtOAc/cyc 3:1).

Yield: 3.64 g (84% of theory)

ESI-MS: (M+H)⁺=622/624/626 (2 Br)

retention time (HPLC): 10.0 min (method A)

1g (R)-2-(3,4-dibromo-phenyl)-1-hydroxycarbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 210 mg (9 mmol) LiOH.6H₂O in 40 mL water was added at RTto a solution of 3.64 g (5.83 mmol) of(R)-2-(3,4-dibromo-phenyl)-1-ethoxycarbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylatein 70 mL THF and the reaction mixture was stirred for 7 h at RT. Themixture was evaporated down i.vac., the residue was taken up in 100 mLwater, 1 M HCl was added until an acid reaction was obtained, theprecipitate was filtered off and dried in the vacuum drying chamber at50° C. The product was reacted further without purification.

Yield: 3.36 g (97% of theory)

ESI-MS: (M+H)⁺=594/596/598 (2 Br)

retention time (HPLC): 8.5 min (method A)

1h(R)-1-(3,4-dibromo-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 80 mg (0.13 mmol) of(R)-2-(3,4-dibromo-phenyl)-1-hydroxycarbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,43.2 mg (0.13 mmol) TBTU and 37 μL (0.27 mmol) triethylamine in 1.5 mLDMF was stirred for 1 h at RT. Then 24.9 mg (0.134 mmol) of1-(1-methyl-piperidin-4-yl)-piperazine were added and the reactionmixture was then stirred overnight at RT. The reaction solution wasfiltered through an injection filter and purified directly by HPLCwithout any further working up. The fractions containing the productwere combined and lyophilised.

Yield: 87.6 mg (87% of theory)

ESI-MS: (M+H)⁺=759/761/763 (2 Br)

retention time (HPLC): 5.0 min (method A)

The following compounds were prepared analogously from in each case 80mg of (R)-2-(3,4-dibromo-phenyl)-1-hydroxycarbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand the corresponding amount of amine:

Retention time Mass- HPLC Example R Yield (%) spectrum (method) 2

69 759/761/763[M + H]⁺ 5.6 min(A) 3

72 758/760/762[M + H]⁺ 6.0 min(A) 4

59 744/746/748[M + H]⁺ 6.2 min(A) 5

71 704/706/708[M + H]⁺ 5.8 min(A) 6

21 773/775/777[M + H]⁺ 5.4 min(A) 7

70 773/775/777[M + H]⁺ 5.1 min(A) 8

69 845/847/849[M + H]⁺ 6.6 min(A) 9

59 845/847/849[M + H]⁺ 6.7 min(A)

The following compounds may be prepared analogously from4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(R)-2-(3,4-dibromo-phenyl)-1-hydroxycarbonyl-ethyl and the correspondingamount of amine:

Example R 10

11

12

13

14

15

16

17

18

Example 19(R)-1-(3,4-dibromo-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 125 mg (0.15 mmol) of(R)-1-(3,4-dibromo-benzyl)-2-[4-(1-tert-butoxycarbonyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylatein 20 mL 2 M HCl was stirred for 16 h at RT. The reaction mixture waslyophilised, and the product was obtained as the bis-hydrochloride salt.

Yield: 110 mg (91% of theory)

ESI-MS: (M+H)⁺=745/747/749 (2 Br)

retention time (HPLC): 5.4 min (method A)

Example 20(R)-1-(3,4-dibromo-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 79 mg (0.09 mmol) tert-butyl4-(1-{(R)-3-(3,4-dibromo-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-piperidin-4-yl)-piperazine-1-carboxylatein 15 mL 2 M HCl was stirred for 16 h at RT. The reaction mixture waslyophilised, and the product was obtained as the bis-hydrochloride salt.

Yield: 76 mg (100% of theory)

ESI-MS: (M+H)⁺=745/747/749 (2 Br)

retention time (HPLC): 5.7 min (method A)

Example 21(R)-1-(3,4-dichloro-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

21a 2-acetylamino-3-(3,4-dichloro-phenyl)-acrylic acid

A mixture of 20.0 g (112 mmol) 3,4-dichlorobenzaldehyde, 19.7 g (168mmol) N-acetylglycine and 13.8 g (168 mmol) NaOAc in 80 mL aceticanhydride were heated to 120° C. (oil bath temperature) for 5 h. Afterthe reaction had ended the reaction mixture was cooled using an ice bathand then combined slowly with 60 mL water (slightly exothermicreaction). The reaction mixture was heated to 80° C. for a further 1.5h, cooled somewhat, then added to a mixture of 400 mL water and 200 mLtoluene and stirred overnight at RT. The precipitate was suctionfiltered, washed with toluene and water, then combined with diethylether and suction filtered.

Yield: 21.0 g (68% of theory)

ESI-MS: (M+H)⁺=274/276/278 (2 Cl)

R_(f)=0.16 (silica gel, DCM/MeOH/NH₃ 80:20:2)

21b 3-(3,4-dichloro-phenyl)-2-oxo-propionic acid

140 mL 4 M HCl were added to a suspension of 21.0 g (76.6 mmol)2-acetylamino-3-(3,4-dichloro-phenyl)-acrylic acid in 100 mLN-methyl-2-pyrrolidinone and the reaction mixture was then heated for 4h at an oil bath temperature of 125° C. The cooled reaction solution waspoured onto a cooled mixture of 350 mL water and 120 mL toluene. Thephases were separated, the aqueous phase was again extracted withtoluene, the combined organic phases were extracted with water, filteredthrough Na₂SO₄ and evaporated down i. vac. The residue was taken up in 1M NaOH and washed twice with diethyl ether. The aqueous phase wasacidified with 2 M HCl and extracted three times with EtOAc . Thecombined organic phases were filtered through Na₂SO₄ and evaporated downi. vac. The residue was combined with diethyl ether, suction filteredand dried in the vacuum drying cupboard.

Yield: 8.20 g (46% of theory)

ESI-MS: (M+H)⁺=231/233/235 (2 Cl)

R_(f)=0.11 (silica gel, DCM/MeOH/cyc/NH₃ 70:15:15:2)

21c (R)-3-(3,4-dichloro-phenyl)-2-hydroxy-propionic acid

A solution of 12.2 g (38.0 mmol) (1 R)-B-chlorodiisopinocampheylboranein 20 mL THF was added dropwise within 30 min to a solution of 8.0 g(34.3 mmol) 3-(3,4-dichloro-phenyl)-2-oxo-propionic acid and 5.2 mL(38.0 mmol) triethylamine in 40 mL THF cooled to −35° C. and thereaction mixture was kept for 1 h at this temperature. The cooling bathwas removed and the reaction solution was stirred for 4 h at RT. Thenthe reaction solution was carefully combined with 50 mL 1 M NaOH(exothermic) and 30 mL TBME at 5-10° C. and stirred for 15 min. Theorganic phase was separated off and extracted with 25 mL water and 15 mL1 M NaOH. The combined aqueous phases were acidified with 2 M HCl andextracted three times with in each case 40 mL TBME. The combined organicphases were dried over Na₂SO₄ and evaporated down i. vac. The residuewas dissolved in 80 mL boiling water and suction filtered throughCelite. The filtrate was saturated with NaCl and extracted three timeswith EtOAc. The combined organic phases were filtered through Na₂SO₄ andagain evaporated down i. vac. The crude product was further reactedwithout purification.

Yield: 3.9 g (48% of theory)

ESI-MS: (M+H)⁺=233/235/327 (2 Cl)

retention time (HPLC): 6.8 min (method A)

R_(f)=0.87 (silica gel, DCM/MeOH/cyc/NH₃ 70:15:15:2)

21d ethyl (R)-3-(3,4-dichloro-phenyl)-2-hydroxy-propionate

50 mL ethanolic HCl were added to a solution of 3.5 g (14.9 mmol) of(R)-3-(3,4-dichloro-phenyl)-2-hydroxy-propionic acid in 50 mL EtOH andthe reaction mixture was stirred for 4 h at RT. The reaction solutionwas evaporated down i. vac., the residue was combined with DCM,extracted with 15% K₂CO₃ solution and the organic phase was dried overNa₂SO₄. After the desiccant and solvent had been eliminated the productwas obtained as an oil, which was further reacted without purification.

Yield: 2.6 g (66% of theory)

ESI-MS: (M+H)⁺=263/265/267 (2 Cl)

R_(f)=0.91 (silica gel, DCM/MeOH/cyc/NH₃ 70:15:15:2)

21e (R)-2-(3,4-dichloro-phenyl)-1-ethoxycarbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

450 mg (55% in mineral oil, 10.3 mmol) NaH were added batchwise to asolution of 2.6 g (9.9 mmol) ethyl(R)-3-(3,4-dichloro-phenyl)-2-hydroxy-propionate in 50 mL THF cooled to0° C. and stirred for a further 30 min at this temperature. Subsequently3.7 g (11.9 mmol)4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonylchloridewere added batchwise while being cooled and the reaction mixture wasstirred overnight at RT. The reaction solution was evaporated downi.vac., the residue combined with DCM, the organic phase was separatedoff, washed with 10% citric acid solution and 15% K₂CO₃ solution anddried over Na₂SO₄. After the desiccant and solvent had been eliminatedthe product was obtained which was reacted without any furtherpurification.

Yield: 5.2 g (98% of theory)

ESI-MS: (M+H)⁺=534/536/538 (2 Cl)

R_(f)=0.77 (silica gel, DCM/MeOH/cyc/NH₃ 70:15:15:2)

21f 1-carboxy-(R)-2-(3,4-dichloro-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

a solution of 348 mg (14.5 mmol) lithium hydroxide in 10 mL water wasadded at RT to a solution of 5.2 g (9.7 mmol)2-(3,4-dichloro-phenyl)-1-ethoxy-carbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-(R)-carboxylatein 30 mL THF and the reaction mixture was stirred overnight at RT. Itwas evaporated down i. vac., the residue was taken up in 15% K₂CO₃solution and the aqueous phase was washed three times with EtOAc. Theaqueous phase was mixed with 5 M HCl with stirring until an acidreaction was obtained and extracted exhaustively with DCM. The combinedorganic phases were filtered through Na₂SO₄ and the solvent waseliminated i. vac. The residue was taken up in isopropanol and theprecipitate was filtered off. The filtrate was evaporated down i.vac.,the residue was purified by chromatography (silica gel, gradientDCM/MeOH/NH₃ 10:0:0 to 75:25:5), the corresponding fractions werecombined, the solvent was eliminated, the residue was combined withdiethyl ether and suction filtered.

Yield: 2.2 g (45% of theory)

ESI-MS: (M+H)⁺=506/508/510 (2 Cl)

R_(f)=0.51 (silica gel, DCM/MeOH/cyc/NH₃ 70:15:15:2)

21g(R)-1-(3,4-dichloro-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 80 mg (0.16 mmol)1-carboxy-(R)-2-(3,4-dichloro-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,58 mg (0.18 mmol) TBTU and 25 μL (0.18 mmol) triethylamine in 2 mL DMFwas stirred for 10 min at RT. Then 33 mg (0.18 mmol) of1-(1-methyl-piperidin-4-yl)-piperazine were added and the reactionmixture was stirred overnight at RT. The reaction solution was filteredthrough an injection filter and purified directly by HPLC without anyfurther working up. The fractions containing the product were combinedand lyophilised.

Yield: 35.0 mg (33% of theory)

ESI-MS: (M+H)⁺=671/673/675 (2 Cl)

retention time (HPLC): 5.3 min (method A)

The following compounds were obtained analogously from in each case 80mg (Examples 22 to 24) or 160 mg (Examples 25 to 27) of1-carboxy-(R)-2-(3,4-dichloro-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetra-hydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand the corresponding amount of amine:

Retention time Mass HPLC Example R Yield (%) spectrum (method) 22

33 671/673/675[M + H]⁺ 5.8 min(A) 23

29 656/658/660[M + H]⁺ 6.5 min(A) 24

38 670/672/674[M + H]⁺ 6.2 min(A) 25

13 757/759/761[M + H]⁺ 7.0 min(A) 26

15 757/759/761[M + H]⁺ 6.9 min(A) 27

13 n.e. 5.0 min(A)

Example 28(R)-1-3,4-dichloro-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 30 mg (0.04 mmol) of(R)-1-(3,4-dichloro-benzyl)-2-[4-(1-tert-butoxycarbonyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 25) in 5 mL 4 M HCl was stirred overnight at RT. The reactionmixture was lyophilised, and the product was obtained as the HCl salt.

Yield: 18 mg (66% of theory)

ESI-MS: (M+H)⁺=657/659/661 (2 Cl)

R_(f)=0.33 (silica gel, DCM/MeOH/cyc/NH₃ 70:15:15:2)

Example 29(R)-1-(3,4-dichloro-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 35 mg (0.05 mmol) tert-butyl4-(1-{(R)-3-(3,4-dichloro-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-piperidin-4-yl)-piperazine-1-carboxylate(Example 26) in 5 mL 4 M HCl was stirred overnight at RT. The reactionmixture was lyophilised, and the product was obtained as the HCl salt.

Yield: 24 mg (75% of theory)

ESI-MS: (M+H)⁺=657/659/661 (2 Cl)

R_(f)=0.30 (silica gel, DCM/MeOH/cyc/NH₃ 70:15:15:2)

Example 30(R)-2-4,4′-bipiperidinyl-1-yl-1-(3,4-dichloro-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 30 mg (0.04 mmol) tert-butyl1′-{(R)-3-(3,4-dichloro-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-4,4′-bipiperidinyl-1-carboxylate(Example 27) in 5 mL 4 M HCl was stirred overnight at RT. The reactionmixture was lyophilised, and the product was obtained as the HCl salt.

Yield: 16 mg (58% of theory)

ESI-MS: (M+H)⁺=656/658/660 (2 Cl)

Example 31(R)-1-(4-chloro-3,5-dimethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

31a 5-bromo-2-chloro-1,3-dimethylbenzene

40.0 g (200 mmol) 4-bromo-2,6-dimethylamine in 100 mL semiconc. HCl werecombined at 0° C. with 15.2 g (220 mmol) NaNO₂ in 90 mL water, stirredfor 20 min, combined with a solution of 21.7 g (220 mmol) CuCl in 90 mLsemiconc. HCl and stirred for 2 h at 70° C. and for 15 h at RT. Afterthe reaction had ended the reaction mixture was poured onto 200 mL waterand extracted with TBME. The organic phases were combined, extractedwith 2 M NaOH until the organic phase remained colourless and thecombined organic phases were then dried over Na₂SO₄. After the desiccantand solvent had been eliminated the residue was purified bychromatography (silica gel, cyc/DCM 1:1).

Yield: 30.7 g (70% of theory)

ESI-MS: (M+H)⁺=218/220/222 (Br, Cl)

R_(f)=0.84 (silica gel, cyc/DCM 1:1)

31b methyl 2-acetylamino-3-(4-chloro-3,5-dimethyl-phenyl)-acrylate

Under a nitrogen atmosphere 30.0 g (136.7 mmol)5-bromo-2-chloro-1,3-dimethylbenzene, 24.0 g (164.0 mmol) methyl2-acetylamino-acrylate in 420 mL triethylamine and 200 mL acetonitrilewere combined with 3.4 g (10.9 mmol) tri-o-tolyl-phosphane and 2.4 g(10.9 mmol) Pd(OAc)₂ and stirred for 18 h at 80° C. The precipitate wassuction filtered, the filtrate was evaporated down i. vac., combinedwith 800 mL DCM and 800 mL water, the organic phase was separated offand dried over Na₂SO₄. After the desiccant and solvent had beeneliminated the residue was stirred with EtOAc, suction filtered anddried i. vac.

Yield: 29.4 g (76% of theory)

ESI-MS: (M+H)⁺=282/284 (Cl)

retention time (HPLC-MS): 7.8 min (method A)

31c 3-(4-chloro-3,5-dimethyl-phenyl)-2-oxo-propionic acid

29.4 g (105 mmol) methyl2-acetylamino-3-(4-chloro-3,5-dimethylphenyl)-acrylate in 330 mLN-methyl-2-pyrrolidinone were combined with 500 mL cooled 4 M HCl,stirred for 6 h at reflux temperature and for 16 h at RT. After thereaction had ended the reaction mixture was poured onto 1650 mL water,stirred for 1 h, suction filtered and the crystals were dried at 50° C.in the vacuum drying cupboard. The product was recrystallised fromtoluene.

Yield: 12.3 g (52% of theory)

ESI-MS: (M+H)⁺=225/227 (Cl)

retention time (HPLC-MS): 7.9 min (method A)

31d (R)-3-(4-chloro-3,5-dimethyl-phenyl)-2-hydroxy-propionic acid

12.3 g (54.4 mmol) 3-(4-chloro-3,5-dimethyl-phenyl)-2-oxo-propionic acidin 130 mL THF and 7.6 mL (54.4 mmol) triethylamine were combined at -35°C. with a solution of 21.0 g (65.3 mmol)(1R)-B-chlorodiisopinocampheylborane in 65 mL THF within 30 min andstirred for 2 h at this temperature. After the reaction had ended thereaction mixture was made alkaline at 0° C. with 50 mL 1 M NaOH(exothermic), stirred for 3 h, combined with 30 mL TBME and the phaseswere separated. The organic phase was washed with 50 mL water and 30 mL1 M NaOH. The combined aqueous phases were acidified with 2 M HCl andextracted with TBME. The organic phases were dried over Na₂SO₄ andevaporated down i. vac. The product was reacted further withoutpurification.

Yield: 12.5 g (100% of theory)

ESI-MS: (M+H)⁺=227/229 (Cl)

retention time (HPLC-MS): 7.1 min (method A)

31e methyl (R)-3-(4-chloro-3,5-dimethyl-phenyl)-2-hydroxy-propionate

4.4 mL (59.9 mmol) SOCl₂ were added dropwise to a solution of 12.45 g(54.4 mmol) of (R)-3-(4-chloro-3,5-dimethyl-phenyl)-2-hydroxy-propionicacid in 300 mL MeOH cooled to 0° C. and the reaction mixture was stirredfor 1 h at RT. The reaction solution was evaporated down i. vac. and theresidue was purified by chromatography (silica gel, cyc/EtOAc 4:1).

Yield: 10.1 g (76% of theory)

ESI-MS: (M+NH₄)⁺=260/262 (Cl)

retention time (HPLC-MS): 8.1 min (method A)

31f (R)-2-(4-chloro-3,5-dimethyl-phenyl)-1-methoxycarbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Under a nitrogen atmosphere 1.0 g (8.2 mmol) 4-dimethylaminopyridine in30 mL pyridine were combined with 1.7 g (8.2 mmol) 4-nitrophenylchloroformate, stirred for 40 min at RT, then 2.0 g (8.2 mmol) methyl(R)-3-(4-chloro-3,5-dimethyl-phenyl)-2-hydroxy-propionate were added,the mixture was again stirred for 20 min at RT and then combined with2.0 g (8.2 mmol)3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and thereaction mixture was stirred for 20 h at RT. The mixture was evaporateddown i.vac., the residue was taken up in EtOAc, washed with 10% KHSO₄and saturated NaHCO₃ solution and the organic phase was dried over.After the desiccant and solvent had been eliminated the residue waspurified by chromatography (silica gel, cyc/EtOAc 1:1 to 1:2).

Yield: 2.16 g (51% of theory)

ESI-MS: (M+H)⁺=514/516 (Cl)

retention time (HPLC-MS): 10.1 min (method A)

31g (R)-1-carboxy-2-(4-chloro-3,5-dimethyl-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 150 mg (0.60 mmol) LiOH in 30 mL water was added to asolution of 2.15 g (4.18 mmol) of(R)-2-(4-chloro-3,5-dimethyl-phenyl)-1-methoxycarbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylatein 60 mL THF and the reaction mixture was stirred for 1 h at RT. Themixture was evaporated down in vacuo, the residue was taken up in 100 mLwater, acidified with 1 M HCl, the precipitate was filtered and dried inthe vacuum drying cupboard at 40° C.

Yield: 2.05 g (98% of theory)

ESI-MS: (M+H)⁺=500/502 (Cl)

retention time (HPLC-MS): 8.8 min (method A)

31h(R)-1-(4-chloro-3,5-dimethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 80 mg (0.16 mmol) of(R)-2-(4-chloro-3,5-dimethyl-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-benzodiazepin-3-yl)-piperidine-1-carboxylate,51 mg (0.16 mmol) TBTU and 28 μL (0.20 mmol) triethylamine in 1.5 mL DMFwas stirred for 1 h at RT. Then 30 mg (0.16 mmol)1-methyl-4-(piperidin-4-yl)-piperazine were added and the reactionmixture was stirred for 16 h at RT. The reaction solution was filteredthrough an injection filter and purified directly by HPLC without anyfurther working up. The fractions containing the product were combinedand lyophilised.

Yield: 18 mg (17% of theory)

ESI-MS: (M+H)⁺=665/667 (Cl)

retention time (HPLC-MS): 5.6 min (method A)

The following compounds were obtained analogously from in each case 80mg (Examples 32 to 34) or in each case 140 mg (Examples 35 and 36) of(R)-1-carboxy-2-(4-chloro-3,5-dimethyl-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand the corresponding amount of amine:

retention time Mass HPLC Example R Yield (%) spectrum (method) 32

40 665/667(Cl)[M + H]⁺ 5.3 min(A) 33

42 664/666(Cl)[M + H]⁺ 6.8 min(A) 34

44 610/612(Cl)[M + H]⁺ 6.5 min(A) 35

30 751/753(Cl)[M + H]+ 7.5 min(A) 36

28 751/753(Cl)[M + H]+ 7.7 min(A)

Example 37(R)-1-(4-chloro-3,5-dimethyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 64.0 mg (0.09 mmol) tert-butyl4-(1-{(R)-3-(4-chloro-3,5-dimethyl-phenyl)-2-[4-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-piperidin-4-yl)-piperazine-1-carboxylate(Example 35) in 5 mL 2 M HCl was stirred overnight at RT. The reactionmixture was lyophilised, and the product was obtained as thebis-hydrochloride salt.

Yield: 61.2 mg (99% of theory)

ESI-MS: (M+H)⁺=651/653 (Cl)

retention time (HPLC-MS): 5.9 min (method A)

Example 38(R)-1-(4-chloro-3,5-dimethyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 59 mg (0.08 mmol) of(R)-1-(4-chloro-3,5-dimethyl-benzyl)-2-[4-(1-tert-butoxy-carbonyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 36) in 5 mL of 2 M HCl was stirred overnight at RT. Thereaction mixture was lyophilised, and the product was obtained as thebis-hydrochloride salt.

Yield: 55.7 mg (57% of theory)

ESI-MS: (M+H)⁺=651/653 (Cl)

retention time (HPLC-MS): 5.5 min (method A)

Example 39(R)-1-(3,5-dimethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

39a (R)-1-carboxy-2-(3,5-dimethyl-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

500 mg (1.0 mmol) 1-carboxy-(R)-2-(4-chloro-3,5-dimethyl-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 31g) in 20 mL MeOH were combined with 100 mg 10% Pd/C and 2 mLtriethylamine and hydrogenated for 10 days at RT and 3 bar. After thereaction had ended the reaction mixture was evaporated down i.vac., theresidue was taken up in 25 mL water, acidified with 1 M HCl, theprecipitate was suction filtered and dried in the vacuum drying cupboardat 40° C.

Yield: 418 mg (90% of theory)

ESI-MS: (M+H)⁺=466

retention time (HPLC-MS): 8.3 min (method A)

39b(R)-1-(3,5-dimethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 50 mg (0.16 mmol) of(R)-1-carboxy-2-(3,5-dimethyl-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,35 mg (0.11 mmol) TBTU and 19 μL (0.13 mmol) triethylamine in 1 mL DMFwas stirred for 1 h at RT. Then 20 mg (0.11 mmol)1-(1-methyl-piperidin-4-yl)-piperazine were added and the reactionmixture was stirred for 16 h at RT. The reaction solution was filteredthrough an injection filter and purified directly by HPLC without anyfurther working up. The fractions containing the product were combinedand lyophilised.

Yield: 33 mg (49% of theory)

ESI-MS: (M+H)⁺=631

retention time (HPLC-MS): 5.3 min (method A)

The following compounds were obtained analogously from in each case 50mg (Examples 40 and 41) or in each case 80 mg (Examples 42 and 43)(R)-1-carboxy-2-(3,5-dimethyl-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand the corresponding amount of amine:

retention time HPLC (method) or R_(f) Mass (silica gel, Example R Yield(%) spectrum eluant 40

76 631[M + H]⁺ 5.8 min(A) 41

55 630[M + H]⁺ 6.5 min(A) 42

37 717[M + H]⁺ 4.7 min(A) 43

73 716[M + H]⁺ 0.59(EtOAc)

Example 44(R)-1-(3,5-dimethyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 45 mg (0.06 mmol) of(R)-1-(3,5-dimethyl-benzyl)-2-[4-(1-tert-butoxy-carbonyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 42) in 10 mL 2 M HCl was stirred overnight at RT. The reactionmixture was lyophilised. The crude product was taken up in 1 mL DMF,made alkaline with 0.6 mL saturated K₂CO₃ solution and purifiedchromatographically by HPLC.

Yield: 26.8 mg (69% of theory)

ESI-MS: (M+H)⁺=617

retention time (HPLC-MS): 5.4 min (method A)

Example 45(R)-2-[4,4′]bipiperidinyl-1-yl-1-(3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 101 mg (0.14 mmol) tert-butyl1′-{(R)-3-(3,5-dimethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-4,4′-bipiperidinyl-1-carboxylate(Example 43) in 10 mL 2 M HCl was stirred overnight at RT. The reactionmixture was lyophilised. The crude product was taken up in 1 mL DMF,made alkaline with 0.6 mL saturated K₂CO₃ solution and purifiedchromatographically by HPLC.

Yield: 18.7 mg (22% of theory)

ESI-MS: (M+H)⁺=616

retention time (HPLC-MS): 6.5 min (method A)

Example 46(R)-1-(3,5-bis-trifluoromethylbenzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

46a methyl 2-acetylamino-3-(3,5-bis-trifluoromethyl-phenyl)acrylate

Under a nitrogen atmosphere 50.0 g (171 mmol)3,5-bis-(trifluoromethyl)-bromobenzene, 25.0 g (171 mmol) methyl2-acetylamino-acrylate in 475 mL triethylamine and 250 mL acetonitrilewere combined with 3.9 g (12.4 mmol) tri-o-tolyl-phosphane and 2.8 g(12.5 mmol) Pd(OAc)₂ and stirred for 18 h at 80° C. After the reactionhad ended the reaction mixture was evaporated down i. vac. to approx.200 mL, combined with 400 mL EtOAc and 400 mL water, the precipitate wassuction filtered and the phases were separated. The organic phase wasdried over Na₂SO₄, combined with activated charcoal, filtered andevaporated to dryness. The residue was stirred with DIPE, suctionfiltered and dried i. vac.

Yield: 19.5 g (32% of theory)

ESI-MS: (M+H)⁺=356

R_(f)=0.76 (silica gel, PE/EtOAc 1:1)

46b 3-(3,5-bis-trifluoromethyl-phenyl)-2-oxo-propionic acid

19.5 g (54.9 mmol) methyl2-acetylamino-3-(3,5-bis-trifluoromethyl-phenyl)-acrylate in 100 mL1,4-dioxane were heated to 100° C. bath temperature, combined with 100mL 4 M HCl and stirred for 8 h at 100° C. bath temperature. The reactionmixture was evaporated down i. vac., the crystals were suction filtered,washed with water and dried in the drying cupboard at 50° C.

Yield: 16.1 g (98% of theory)

ESI-MS: (M−H)⁻=299

R_(f)=0.18 (silica gel, EtOAc)

46c (R)-3-(3,5-bis-trifluoromethyl-phenyl)-2-hydroxy-propionic acid

16.1 g (53.6 mmol) 3-(3,5-bis-trifluoromethyl-phenyl)-2-oxo-propionicacid in 9.5 (70.0 mmol) triethylamine and 100 mL THF were combined at−35° C. with a solution of 26.0 (81.1 mmol)(1R)-B-chlorodiisopinocampheylborane in 40 mL THF within 30 min, stirredfor 1 h at this temperature and stirred overnight at RT. After thereaction had ended the reaction mixture was made alkaline at 0° C. with160 mL 1 M NaOH, stirred for 15 min, combined with 100 mL TBME and thephases were separated. The organic phase was washed with 50 mL water and50 mL 1 M NaOH. The combined aqueous phases were acidified with 4 M HCl,exhaustively extracted with TBME, the combined organic phases were driedover Na₂SO₄, suction filtered through activated charcoal and evaporateddown i.vac. The product was reacted further without purification.

Yield: 12.5 g (77% of theory)

ESI-MS: (M−H)⁻=301

R_(f)=0.45 (silica gel, EtOAc)

46d methyl (R)-3-(3,5-bis-trifluoromethyl-phenyl)-2-hydroxy-propionate

12.5 g (41.4 mmol) of(R)-3-(3,5-bis-trifluoromethyl-phenyl)-2-hydroxy-propionic acid in 150mL methanolic HCl (1.25 M) were stirred for 4 h at RT and thenevaporated down i. vac. The residue was taken up in EtOAc and washedwith saturated NaHCO₃ solution, the organic phase was dried over Na₂SO₄,suction filtered through activated charcoal and evaporated down i. vac.The residue was stirred with PE, suction filtered and evaporated down i.vac. The product was reacted further without purification.

Yield: 11.4 g (87% of theory)

ESI-MS: (M+H)⁺=316

R_(f)=0.80 (silica gel, PE/EtOAc 1:1)

46e (R)-2-(3,5-bis-trifluoromethyl-phenyl)-1-methoxycarbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Analogously to Example 31f the product was obtained from 6.0 g (8.2mmol) methyl (R)-3-(3,5-bis-trifluoromethyl-phenyl)-2-hydroxy-propionateand 5.13 g (20.9 mmol)3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one.Purification was carried out by chromatography (silica gel, gradientPE/EtOAc 1:1 to 1:9).

Yield: 5.1 g (46% of theory)

ESI-MS: (M+H)⁺=588

R_(f)=0.63 (silica gel, DCM/MeOH/cyc/NH₃ 70:15:15:2)

46f (R)-2-(3,5-bis-trifluoromethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 307 mg (12.8 mmol) LiOH in 5 mL water was added to asolution of 5.0 g (8.5 mmol) of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-1-methoxy-carbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylatein 50 mL THF and the reaction mixture was stirred overnight at RT. Themixture was evaporated down in vacuo, the residue was taken up in water,acidified with 1 M HCl, the precipitate was filtered off and dried inthe vacuum drying cupboard at 40° C.

Yield: 4.5 g (92% of theory)

ESI-MS: (M+H)⁺=574

R_(f)=0.32 (silica gel,DCM/MeOH/cyc/NH₃ 70:15:15:2)

46g(R)-1-(3,5-bis-trifluoromethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 80 mg (0.14 mmol) of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-benzodiazepin-3-yl)-piperidine-1-carboxylate,51 mg (0.16 mmol) TBTU and 22 μL (0.16 mmol) triethylamine in 1 mL DMFwas stirred for 1 h at RT. Then 29 mg (0.16 mmol)1-(1-methyl-piperidin-4-yl)-piperazine were added and the reactionmixture was stirred overnight at RT. The reaction solution was filteredthrough an injection filter and purified directly by HPLC without anyfurther working up. The fractions containing the product were combinedand lyophilised.

Yield: 56 mg (54% of theory)

ESI-MS: (M+H)⁺=739

retention time (HPLC-MS): 5.8 min (method A)

The following compounds were obtained analogously from in each case 80mg (Examples 47 to 49) or in each case 100 mg (Examples 50 to 53)(R)-2-(3,5-bis-trifluoromethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-benzodiazepin-3-yl)-piperidine-1-carboxylateand the corresponding amount of amine:

retention time Mass HPLC Example R Yield (%) spectrum (method) 47

49 739[M + H]⁺ 6.5 min(A) 48

47 738[M + H]⁺ 7.1 min(A) 49

57 724[M + H]⁺ 7.1 min(A) 50

39 810[M + H]+ 7.3 min(A) 51

53 815[M + H]+ 6.4 min(A) 52

46 815[M + H]+ 6.1 min(A) 53

65 814[M + H]+ 7.9 min(A)

Example 54(R)-1-(3,5-bis-trifluoromethyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 77 mg (0.09 mmol) of(R)-2-[4-(1-benzyl-piperidin-4-yl)-piperazin-1-yl]-1-(3,5-bis-trifluoromethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 51) in 10 mL MeOH was combined with 50 mg 10% Pd/C and shakenfor 3 h at RT and 50 psi hydrogen. The catalyst was suction filtered,the solvent was evaporated down i.vac., the residue was combined withacetonitrile and water and lyophilised.

Yield: 46 mg (70% of theory)

ESI-MS: (M+H)⁺=725

retention time (HPLC-MS): 5.7 min (method A)

Example 55(R)-1-(3,5-bis-trifluoromethyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 64 mg (0.08 mmol) of(R)-2-[4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-1-(3,5-bis-trifluoromethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 52) in 10 mL MeOH was combined with 50 mg 10% Pd/C and shakenfor 3 h at RT and 50 psi hydrogen. The catalyst was suction filtered,the solvent was evaporated down i.vac., the residue was combined withacetonitrile and water and lyophilised.

Yield: 43 mg (76% of theory)

ESI-MS: (M+H)⁺=725

retention time (HPLC-MS): 5.7 min (method A)

Example 56(R)-2-(4,4′-bipiperidinyl-1-yl)-1-(3,5-bis-trifluoromethyl-benzyl)-2-oxo-2-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 92 mg (0.11 mmol) of(R)-2-(1′-benzyl-4,4′-bipiperidinyl-1-yl)-1-(3,5-bis-trifluoro-methyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 53) in 10 mL MeOH was combined with 50 mg 10% Pd/C and shakenfor 3 h at RT and 50 psi hydrogen. The catalyst was suction filtered,the solvent was evaporated down i.vac., the residue was combined withacetonitrile and water and lyophilised.

Yield: 55 mg (67% of theory)

ESI-MS: (M+H)⁺=724

retention time (HPLC-MS): 5.6 min (method A)

Example 57(R)-1-(3,5-bis-trifluoromethyl-benzyl)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 1.5 mg (0.06 mmol) LiOH in 1 mL water was added to asolution of 35 mg (0.04 mmol) of(R)-1-(3,5-bis-trifluoromethyl-benzyl)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 50) in 5 mL THF and the reaction solution was stirred overnightat RT. The mixture was evaporated down in vacuo, the residue was takenup in water, acidified with 1 N HCl, the precipitate was filtered offand dried in the vacuum drying cupboard.

Yield: 15 mg (44% of theory)

ESI-MS: (M+H)⁺=782

R_(f)=0.41 (silica gel, DCM/MeOH/cyc/NH₃ 70:15:15:2)

Example 58(R)-1-(3,5-dibromo-benzyl)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

58a (Z,E)-2-acetylamino-3-(3,5-dibromo-phenyl)-acrylic acid

Analogously to Example 1a the product was obtained from 35.0 g (133mmol) 3,5-dibromo-benzaldehyde and 23.3 g (199 mmol) N-acetyl-glycine.

Yield: 29.2 g (61% of theory)

melting point: 248-249° C.

ESI-MS (M+H)⁺=362/364/366 (2 Br)

R_(f)=0.1 (silica gel, DCM/MeOH/AcOH 90:10:1)

58b 3-(3,5-dibromo-phenyl)-2-oxo-propionic acid

Analogously to Example 1b the product was obtained from 29.0 g (80.0mmol) (Z,E)-2-acetylamino-3-(3,5-dibromo-phenyl)-acrylic acid.

Yield: 14.0 g (54% of theory)

ESI-MS (M−H)⁻=318/320/322 (2 Br)

R_(f)=0.4 (silica gel, DCM/MeOH/AcOH 90:10:1)

58c (R)-3-(3,5-dibromo-phenyl)-2-hydroxy-propionic acid

Analogously to Example 1c the product was obtained from 12.0 g (37.3mmol) 3-(3,5-dibromo-phenyl)-2-oxo-propionic acid and 15.1 g (47.1 mmol)(1 R)-B-chlorodiisopinocampheylborane.

Yield: 4.1 g (34% of theory)

ESI-MS (M−H)⁻=321/323/325 (2 Br)

58d methyl (R)-3-(3,5-dibromo-phenyl)-2-hydroxy-propionate

Analogously to Example 46d the product was obtained from 4.0 g (12.4mmol) of (R)-3-(3,5-dibromo-phenyl)-2-hydroxy-propionic acid, usingmethanolic HCl (6 M) for the esterification.

Yield: 4.0 g (96% of theory)

R_(f)=0.9 (silica gel, DCM/MeOH/AcOH 90:10:1)

58e (R)-2-(3,5-dibromo-phenyl)-1-methoxycarbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Analogously to Example 31f the product was obtained from 3.40 g (10.06mmol) methyl (R)-3-(3,5-dibromo-phenyl)-2-hydroxy-propionate and 2.46 g(10.03 mmol)3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one.

Yield: 2.0 g (33% of theory)

ESI-MS (M+H)⁺=608/610/612 (2 Br)

R_(f)=0.2 (silica gel, n-hexane/EtOAc 3:7)

retention time (HPLC): 22.6 min (method F)

58f (R)-1-carboxy-2-(3,5-dibromo-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 118 mg (4.9 mmol) LiOH in 5 mL water was added to asolution of 2.0 g (3.3 mmol) of(R)-2-(3,5-dibromo-phenyl)-1-methoxycarbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylatein 12.5 mL THF and the mixture was stirred for 2 h at RT. The reactionmixture was evaporated down i. vac., the residue was combined with waterand TBME, the aqueous phase was adjusted to pH 2-3 with conc. HCl andextracted with DCM. The combined organic phases were washed withsaturated NaCl solution, dried over Na₂SO₄ and evaporated to dryness i.vac.

Yield: 1.9 g (97% of theory)

ESI-MS (M+H)⁺=594/596/598 (2 Br)

R_(f)=0.25 (silica gel, DCM/MeOH 9:1)

retention time (HPLC): 19.1 min (method F)

58g(R)-1-(3,5-dibromo-benzyl)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 150 mg (0.25 mmol) of(R)-1-carboxy-2-(3,5-dibromo-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,90 mg (0.28 mmol) TBTU, 95 μL (0.55 mmol) ethyldiisopropylamine and 38mg (0.28 mmol) HOBt in 6 mL DMF was stirred for 90 min at RT. Then 42 mg(0.33 mmol) 4-dimethylamino-piperidine were added and the reactionmixture was stirred for 16 h at RT. The reaction solution was combinedwith water, the organic phase was evaporated down and the residue waspurified by chromatography (silica gel, DCM/MeOH/NH₃ 95:5:0.5).

Yield: 140 mg (79% of theory)

ESI-MS (M+H)⁺=704/706/708 (2 Br)

R_(f)=0.35 (silica gel, DCM/MeOH/NH₃ 90:10:1)

retention time (HPLC): 12.0 min (method F)

The following compounds were obtained analogously from in each case 150mg (R)-1-carboxy-2-(3,5-dibromo-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand the corresponding amount of amine:

retention time Mass HPLC Example R Yield (%) spectrum (method) 59

73 759/761/763[M + H]⁺ 10.4 min(F) 60

32 744/746/748[M + H]⁺ 12.8 min(F) 61

78 758/760/762[M + H]⁺ 12.9 min(F) 62

67 759/761/763[M + H]⁺  9.3 min(F) 63

91 745/747/749[M + H −Fmoc]⁺ 17.6 min(F) 64

84 845/847/849[M + H]⁺ 14.9 min(F) 65

94 844/846/848[M + H]⁺ 27.2 min(F)

Example 66(R)-1-(3,5-dibromo-benzyl)-2-oxo-2-(4-piperazin-1yl-piperidin-1-yl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 300 mg (0.23 mmol) 9H-fluoren-9-ylmethyl4-(1-{(R)-3-(3,5-dibromo-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-piperidin-4-yl)-piperazine-1-carboxylate(Example 63) in 4 mL piperidine was stirred for 1 h at RT. The reactionsolution was evaporated to dryness and the residue was purified bychromatography (silica gel, gradient DCM to DCM/MeOH/NH₃ 90:10:1).

Yield: 134 mg (79% of theory)

ESI-MS: (M+H)⁺=745/747/749 (2 Br)

retention time (HPLC): 9.7 min (method F)

Example 67(R)-1-(3,5-dibromo-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

1.8 mL HCl (3.2 M) were added to a solution of 180 mg (0.21 mmol) of(R)-1-(3,5-dibromo-benzyl)-2-[4-(1-tert-butoxy-carbonyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 64) in 2 mL water and the reaction mixture was stirred for 3 hat RT. The mixture was combined with 25 mL EtOAc and 20 mL 17% Na₂CO₃solution, the organic phase was separated off, the aqueous phase wasextracted again with 25 mL EtOAc, the combined organic phases werewashed with 10 mL saturated NaCl solution and dried over Na₂SO₄. Afterthe desiccant and solvent had been eliminated the residue was suspendedin diethyl ether, the organic phase was decanted off and the residue wasdried.

Yield: 130 mg (82% of theory)

ESI-MS: (M+H)⁺=745/747/749 (2 Br)

retention time (HPLC): 9.3 min (method F)

Example 68(R)-2-(4,4′-bipiperidinyl-1-yl)-1-(3,5-dibromo-benzyl)-2-oxo-2-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 160 mg (0.19 mmol) tert. butyl1′-{(R)-3-(3,5-dibromo-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-4,4′-bipiperidinyl-1-carboxylate(Example 65) in 2 mL formic acid was stirred for 1 h at RT. The reactionsolution was evaporated down i.vac., the residue was taken up in DCM,the organic phase was washed with 10% Na₂CO₃ solution, filtered andevaporated to dryness. The residue was suspended in 10% NaOH, stirredfor 1 h at RT, the precipitate was filtered, washed with a little waterand diethyl ether and dried i.vac.

Yield: 86 mg (61% of theory)

ESI-MS: (M+H)⁺=744/746/748 (2 Br)

retention time (HPLC): 12.6 min (method F)

Example 69(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

69a 2-benzyloxy-5-bromo-1,3-dimethylbenzene

39.9 g (286 mmol) K₂CO₃ were added to a solution of 50.0 g (249 mmol)2,6-dimethyl-4-bromophenol in 500 mL DMF and stirred for 20 min. Then34.0 mL (286 mmol) benzylchloride were slowly added dropwise and thereaction mixture was stirred for 3 h at 100° C. bath temperature. Afterthe reaction had ended the mixture was poured onto 500 mL water andexhaustively extracted with EtOAc. The organic phases were combined,dried over Na₂SO₄ and evaporated down i. vac.

Yield: quantitative

GC-MS: (M⁺)=290/292 (Br)

R_(f)=0.87 (silica gel, cyc/EtOAc 3:1)

69b methyl 2-acetylamino-3-(4-benzyloxy-3,5-dimethyl-phenyl)-acrylate

Under a nitrogen atmosphere a mixture of 40.0 g (137 mmol)2-benzyloxy-5-bromo-1,3-dimethylbenzene and 24.1 g (165 mmol) methyl2-acetylamino-acrylate in 420 mL triethylamine and 200 mL acetonitrilewas combined with 3.5 g (11.2 mmol) tri-o-tolyl-phosphane and 2.5 g(11.1 mmol) Pd(OAc)₂ and the mixture was stirred for 18 h at 80° C. Theprecipitate was suction filtered, the filtrate was evaporated down i.vac. and combined with 800 mL DCM and 800 mL water. The organic phasewas separated off, suction filtered through Na₂SO₄, the solvent wasremoved i.vac., the residue was stirred with EtOAc, suction filtered anddried i. vac.

Yield: 31.1 g (64% of theory)

ESI-MS: (M+H)⁺=354

retention time (HPLC-MS): 8.6 min (method A)

69c 3-(4-benzyloxy-3,5-dimethyl-phenyl)-2-oxo-propionic acid

31.1 g (88.1 mmol) methyl2-acetylamino-3-(4-benzyloxy-3,5-dimethyl-phenyl)-acrylate in 150 mL1,4-dioxane were combined with 125 mL 4 M HCl, stirred for 7 h at refluxtemperature and stirred overnight at RT. The precipitate was suctionfiltered, washed with water and dried at 45° C. in the vacuum dryingcupboard.

Yield: 14.3 g (54% of theory)

EI-MS: (M)⁺=298

retention time (HPLC-MS): 9.0 min (method A)

69d (R)-3-(4-benzoyl-3,5-dimethyl-phenyl)-2-hydroxy-propionic acid

Under a nitrogen atmosphere a solution of 14.3 g (47.8 mmol)3-(4-benzyloxy-3,5-dimethyl-phenyl)-2-oxo-propionic acid and 8.3 mL(59.8 mmol) triethylamine in 170 mL THF at −35° C. was combined with asolution of 22.1 (69.0 mmol) (1 R)-B-chlorodiisopinocampheylborane in 70mL THF within 30 min. After the addition had ended the cooling bath wasremoved and the reaction solution was stirred overnight at RT. Thereaction mixture was made alkaline at 0° C. with 70 mL 1 M NaOH,combined with 100 mL TBME, stirred for 15 min and the phases wereseparated. The organic phase was washed with 50 mL water and three timeswith 50 mL 1 M NaOH. The combined aqueous phases were acidified withsemiconc. HCl, exhaustively extracted with EtOAc and the combinedorganic phases were dried over Na₂SO₄. After the desiccant and solventhad been eliminated the residue was reacted further withoutpurification.

Yield: 14.0 g (98% of theory)

ESI-MS: (M−H)⁻=299

retention time (HPLC-MS): 7.9 min (method A)

69e methyl (R)-3-(4-benzyloxy-3,5-dimethyl-phenyl)-2-hydroxy-propionate

To a solution cooled to 0° C. of 14.0 g (23.3 mmol) of(R)-3-(4-benzoyl-3,5-dimethyl-phenyl)-2-hydroxy-propionic acid in 150 mLMeOH, 2.0 mL (27.4 mmol) SOCl₂ were added dopwise and the reactionmixture was stirred for 1 h at RT. The reaction solution was evaporateddown i. vac. and the residue was purified by chromatography (silica gel,cyc/EtOAc 3:1).

Yield: 5.7 g (78% of theory)

ESI-MS: (M+NH₄)⁺=332

retention time (HPLC-MS): 9.1 min (method A)

69f (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-methoxycarbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Under a nitrogen atmosphere 1.93 g (9.58 mmol) 4-nitrophenylchloroformate was added to a solution of 1.17 g (9.58 mmol)4-dimethylaminopyridine in 50 mL pyridine, stirred for 1.5 h at RT,combined with 3.0 g (9.58 mmol) methyl(R)-3-(4-benzyloxy-3,5-dimethyl-phenyl)-2-hydroxy-propionate and stirredfor 20 min at RT. Then 2.35 g (9.58 mmol)3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one were addedand the mixture was stirred for 20 h at RT. The reaction mixture wasevaporated down i. vac., the residue was taken up in EtOAc, the organicphase was washed with 10% KHSO₄ and saturated NaHCO₃ solution and driedover Na₂SO₄. After the desiccant and solvent had been eliminated theresidue was purified by chromatography (silica gel, gradient cyc/EtOAc1:1 to 1:2).

Yield: 3.21 g (57% of theory)

ESI-MS: (M+H)⁺=586

retention time (HPLC-MS): 10.4 min (method A)

69g (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 3.21 g (5.48 mmol) of(R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-methoxy-carbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylatein 80 mL THF was combined with a solution of 200 mg (8.35 mmol) LiOH in40 mL water and stirred for 1 h at RT. The reaction mixture wasevaporated down i. vac., the residue was taken up in 100 mL water,acidified with 2 M HCl, the precipitate was suction filtered and driedin the vacuum drying cupboard at 40° C.

Yield: quantitative

ESI-MS: (M+H)⁺=572

retention time (HPLC-MS): 9.2 min (method A)

69h (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

3.72 g (6.51 mmol) of(R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylatein 50 mL DCM were combined with 300 mg 10% Pd/C and shaken at RT and 3bar hydrogen until the reaction came to a stop. The catalyst was suctionfiltered and the solvent was evaporated down i. vac. The residue wastriturated with DIPE and suction filtered.

Yield: 2.41 g (77% of theory)

ESI-MS: (M+H)⁺=482

retention time (HPLC-MS): 7.0 min (method A)

69i(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 70 mg (0.15 mmol) of(R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-i-carboxylate,51 mg (0.16 mmol) TBTU and 26 μL (0.18 mmol) triethylamine in 1 mL DMFwas stirred for 1 h at RT. Then 27 mg (0.15 mmol)1-methyl-4-piperidin-4-yl-piperazine were added and the reaction mixturewas stirred for 16 h at RT. The reaction solution was filtered throughan injection filter and purified directly by HPLC without any furtherworking up. The fractions containing the product were combined andlyophilised.

Yield: 39 mg (42% of theory)

ESI-MS: (M+H)⁺=647

retention time (HPLC-MS): 5.3 min (method A)

The following compounds were obtained analogously from in each case 70mg (Examples 70 to 76),100 mg (Examples 77 and 78) or 400 mg (Example79) of (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand the corresponding amount of amine:

retention time Mass HPLC Example R Yield (%) spectrum (method) 70

47 647[M + H]⁺ 4.9 min(A) 71

41 646[M + H]⁺ 5.8 min(A) 72

32 632[M + H]⁺ 5.8 min(A) 73

38 634[M + H]⁺ 5.6 min(A) 74

39 634[M + H]⁺ 5.7 min(A) 75

37 648[M + H]⁺ 5.5 min(A) 76

38 592[M + H]⁺ 5.6 min(A) 77

21 733[M + H]⁺ 6.4 min(A) 78

36 723[M + H]⁺ 5.3 min(A) 79

71 563[M + H]⁺ 6.9 min(A)

Example 80(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 32 mg (0.04 mmol) tert-butyl4-(1-{(R)-3-(4-hydroxy-3,5-dimethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-piperidin-4-yl)-piperazine-1-carboxylate(Example 77) in 5 mL 2 M HCl was stirred for 20 h at RT and thenlyophilised, the product being obtained as the bis-hydrochloride.

Yield: quantitative

ESI-MS: (M+H)⁺=633

retention time (HPLC-MS): 5.0 min (method A)

Example 81(R)-1-(4hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 54 mg (0.08 mmol) of(R)-2-[4-(1-benzyl-piperidin-4-yl)-piperazin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 78) in 5 mL MeOH were combined with 20 mg of 10% Pd/C andshaken at RT and 3 bar hydrogen until the reaction stopped. The catalystwas suction filtered and the solvent evaporated down i.vac. The residuewas triturated with DIPE, suction filtered and dried under a highvacuum.

Yield: 35.0 mg (74% of theory)

ESI-MS: (M+H)⁺=633

retention time (HPLC-MS): 4.9 min (method A)

Example 82(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(4-hydroxy-4-methyl-[1,4′]bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 50 mg (0.09 mmol) of(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-(4-oxo-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 79) in 1.5 mL DCM was combined with 21 mg (0.18 mmol)4-methyl-piperidin-4-ol and 10.3 μl (0.19 mmol) AcOH, cooled to 0° C.and stirred for 2 h. Then 28 mg (0.19 mmol) sodium-triacetoxyborohydridewere added and the mixture was stirred overnight at 0° C. After thesolvent had been eliminated the residue was combined with 2 mL DMF andpurified by HPLC. The fractions containing the product were combined andlyophilised.

Yield: 25 mg (42% of theory)

ESI-MS: (M+H)⁺=662

retention time (HPLC-MS): 2.90 min (method E)

Example 83(R)-2-(4,4-dimethyl-[1,4′]bipiperidinyl-1′-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Analogously to Example 82 the product was obtained from 50.0 mg (0.09mmol) of(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-(4-oxo-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 79) and 31.0 mg (0.18 mmol) 4,4-dimethylpiperidine.

Yield: 18.3 mg (31% of theory)

ESI-MS: (M+H)⁺=660

retention time (HPLC-MS): 3.2 min (method E)

Example 84(R)-2-(4-amino-4-methyl-[1,4′]bipiperidinyl-1′-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 150 mg (0.27 mmol) of(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-(4-oxo-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 79) in 4 mL DCM was combined with 120 mg (0.53 mmol) tert-butyl(4-methyl-piperidin-4-yl)-carbamate and 31 μL (0.56 mmol) AcOH, cooledto 0° C. and stirred for 2 h. Then 85 mg (0.56 mmol)sodiumtriacetoxyborohydride were added and the mixture was stirredovernight at 0° C. Then the reaction solution was combined with 0.5 mLTFA and again stirred overnight at RT. After elimination of the solventthe residue was dissolved in 2 mL DMF and purified by HPLC. Thefractions containing the product were combined and lyophilised, theproduct being obtained as the TFA salt.

Yield: 94 mg (46% of theory)

ESI-MS: (M+H)⁺=661

retention time (HPLC-MS): 2.50 min (method E)

Example 85(R)-1-(4-amino-3,5-dimethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

85a methyl (Z,E)-2-acetylamino-3-(4-amino-3,5-dimethyl-phenyl)-acrylate

Under a nitrogen atmosphere first of all a solution of 90.0 g (441 mmol)4-bromo-2,6-dimethyl-phenylamine in 200 mL acetonitrile was added to amixture of 7.2 g (32.1 mmol) Pd(OAc)₂ and 10.1 g (32.1 mmol)tri-o-tolyl-phosphane in 1.2 L triethylamine and 600 mL acetonitrile andthen a solution of 65.0 g (445 mmol) methyl 2-acetylamino-acrylate in200 mL acetonitrile was added dropwise. After the addition had ended themixture was stirred for 18 h at 80° C. To complete the reaction thereaction mixture was again combined with 4.0 g (17.8 mmol) Pd(OAc)₂ and5.0 g (16.4 mmol) tri-o-tolyl-phosphane and kept for another 5 h at 80°C. The mixture was evaporated down i.vac to approx. 200 mL, the residuewas combined with 400 mL EtOAc, the residue was filtered (A) and theorganic phase was dried over Na₂SO₄. After elimination of the desiccantby filtration over activated charcoal the filtrate was evaporated downto about 100 mL, the precipitated substance was suction filtered, washedwith 30 mL EtOAc and dried.

The above residue A was combined with 1 L DCM, Na₂SO₄ and activatedcharcoal and filtered through Celite. The filtrate was evaporated down,the residue was combined with 350 mL diethyl ether, the precipitateformed was suction filtered, then washed with 100 mL diethyl ether anddried. The two product fractions were combined.

Yield: 74.8 g (65% of theory)

ESI-MS: (M+H)⁺=263

R_(f)=0.51 (silica gel, EtOAc)

85b 3-(4-amino-3,5-dimethyl-phenyl)-2-oxo-propionic acid

A suspension of 74.0 g (282 mmol) methyl(Z,E)-2-acetylamino-3-(4-amino-3,5-dimethyl-phenyl)-acrylate in 500 mL1,4-dioxane was heated to 100° C. and combined with 460 mL 4 M HCl,whereupon a solution was formed. The mixture was heated for another 8 hat 100° C. and the cooled solution was evaporated down i.vac. to approx.200 mL, during which time the product crystallised out. It was filtered,the residue was washed with 50 mL water and the product was dried at 50°C.

Yield: 43.6 g (63% of theory)

ESI-MS: (M+H)⁺=208

R_(f)=0.68 (silica gel, PE/EtOAc 1:1)

85c methyl (R)-3-(4-amino-3,5-dimethyl-phenyl)-2-hydroxy-propionate

Under a nitrogen atmosphere a mixture of 20.0 g (82.1 mmol)3-(4-amino-3,5-dimethyl-phenyl)-2-oxo-propionic acid and 25.7 mL (189mmol) triethylamine in 400 mL THF was cooled to −35° C. Then a solutionof 40.0 g (125 mmol) (1R)-B-chlorodiisopinocampheylborane in 100 mL THFwas added dropwise so that the reaction temperature remained between−35° C. and −25° C. The reaction mixture was kept for 1 h at thistemperature, the cooling bath was removed and the reaction mixture wasstirred overnight at RT. THF was evaporated down i.vac., the residue wascombined with methanolic HCl (1.25 M) and stirred for 2 h at RT. It wasevaporated down i.vac., the residue was taken up in 2 M HCl andextracted exhaustively with EtOAc. The aqueous phase was made alkalinewith semiconc. NaOH and exhaustively extracted with EtOAc. The combinedorganic phases were dried over Na₂SO₄, suction filtered throughactivated charcoal and evaporated down. The product was obtained as abrown oil.

Yield: 8.3 g (45% of theory)

ESI-MS: (M+H)⁺=224

R_(f)=0.46 (silica gel, PE/EtOAc 1:1)

85d (R)-2-(4-amino-3,5-dimethyl-phenyl)-1-methoxycarbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Analogously to Example 31f the desired product was obtained from 4.0 g(17.9 mmol) methyl(R)-3-(4-amino-3,5-dimethyl-phenyl)-2-hydroxy-propionate and 4.8 g (19.6mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one.

Yield: 3.2 g (36% of theory)

ESI-MS: (M+H)⁺=495

R_(f)=0.35 (silica gel, DCM/MeOH/NH₃ 90:10:1)

85e (R)-2-(4-amino-3,5-dimethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 500 mg (20.9 mmol) LiOH in 10 mL water was added to asolution of 6.7 g (13.6 mmol) of(R)-2-(4-amino-3,5-dimethyl-phenyl)-1-methoxycarbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylatein 50 mL THF and the reaction mixture was stirred overnight at RT. Tocomplete the reaction another 300 mg (12.5 mmol) LiOH were added and thereaction solution was stirred for 3 h at 40° C. It was evaporated downi.vac., the residue was taken up in 15% K₂CO₃ solution and extractedexhaustively with DCM. The aqueous phase was acidified with 4 M HCl,exhaustively extracted with DCM and the combined organic phases weredried over Na₂SO₄. After the desiccant and solvent had been eliminatedthe residue was reacted further without purification.

Yield: 4.2 g (65% of theory)

ESI-MS: (M+H)⁺=481

R_(f)=0.21 (silica gel, DCM/MeOH/cyc/NH₃ 70:15:15:2)

85f(R)-1-(4-amino-3,5-dimethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Analogously to Example 1 h the product was obtained from 80 mg (0.17mmol) of (R)-2-(4-amino-3,5-dimethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand 35 mg (0.19 mmol) 1-methyl-4-piperidin-4-yl-piperazine.

Yield: 50 mg (47% of theory)

ESI-MS: (M+H)⁺=646

retention time (HPLC): 4.9 min (method B)

The following compounds were obtained analogously from in each case 80mg (Examples 86 to 89) or 100 mg (Examples 90 to 92)(R)-2-(4-amino-3,5-dimethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand the corresponding amount of amine:

retention time Mass HPLC Example R Yield (%) spectrum (method) 86

55 646[M + H]⁺ 3.6 min(B) 87

48 645[M + H]⁺ 4.5 min(B) 88

49 633[M + H]⁺ 4.3 min(B) 89

42 631[M + H]⁺ 4.6 min(B) 90

39 717[M + H]⁺ 4.7 min(B) 91

53 732[M + H]⁺ 5.2 min(B) 92

44 732[M + H]⁺ 5.0 min(B)

Example 93(R)-1-(4-amino-3,5-dimethyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 80 mg (0.11 mmol) of(R)-1-(4-amino-3,5-dimethyl-benzyl)-2-[4-(1-tert-butoxy-carbonyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 91) in 2 mL of 4 M HCl was stirred overnight at RT. Thereaction mixture was made alkaline with solid K₂CO₃, exhaustivelyextracted with DCM and the combined organic phases were evaporated downi.vac. Further purification was carried out by HPLC. The fractionscontaining the product were combined and lyophilised.

Yield: 4 mg (6% of theory)

ESI-MS: (M+H)⁺=632

retention time (HPLC): 3.6 min (method A)

Example 94(R)-1-(4-amino-3,5-dimethyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Analogously to Example 93 the product was obtained from 65.0 mg (0.089mmol) tert-butyl4-(1-{(R)-3-(4-amino-3,5-dimethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-piperidin-4-yl)-piperazine-1-carboxylate(Example 92).

Yield: 7 mg (12% of theory)

ESI-MS: (M+H)⁺=632

retention time (HPLC): 3.9 min (method A)

Example 95(R)-1-(4-amino-3,5-dimethyl-benzyl)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 3.1 mg (0.13 mmol) LiOH in 1 mL water was added to asolution of 55 mg (0.08 mmol) of(R)-1-(4-amino-3,5-dimethyl-benzyl)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 90) in 5 mL THF and the reaction mixture was stirred overnightat RT. The mixture was evaporated down i.vac., the residue was taken upin 1 mL DMF and the crude product was purified by HPLC. The fractionscontaining the product were combined and lyophilised.

Yield: 22 mg (42% of theory)

ESI-MS: (M+H)⁺=689

retention time (HPLC): 4.8 min (method A)

Example 96(R)-1-(3-chloro-4-methyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

96a methyl (Z,E)-2-acetylamino-3-(3-chloro-4-methyl-phenyl)-acrylate

Under an argon atmosphere 0.65 g (2.9 mmol) Pd(OAc)₂ and 0.9 g (2.9mmol) tri-o-tolyl-phosphane were added to a mixture of 5.2 mL (39.0mmol) 4-bromo-2-chloro-1-methyl-benzene and 10.0 g (69.9 mmol) methyl2-acetylamino-acrylate in 100 mL each of acetonitrile and triethylamineand the reaction mixture was heated to 90° C. for 20 h. After coolingthe mixture was evaporated down i.vac., the residue was combined withDCM and water, filtered, the organic phase was separated off and driedover Na₂SO₄. After the desiccant and solvent had been eliminated theresidue was purified by chromatography (silica gel, gradient PE/EtOAc1:1 to EtOAc).

Yield: 7.67 g (73% of theory)

ESI-MS: (M+H)⁺=268/270 (Cl)

melting point: 144-145° C.

R_(f)=0.65 (Polygram, EtOAc)

96b 3-(3-chloro-4-methyl-phenyl)-2-oxo-propionic acid

100 mL 4 M HCl were added to a solution of 7.67 g (28.7 mmol) methyl(Z,E)-2-acetylamino-3-(3-chloro-4-methyl-phenyl)-acrylate in 150 mL EtOHand the reaction solution was refluxed for 4 h. The EtOH was removedi.vac., the residue was cooled in the ice bath, while the oily residuesolidified. The solid was filtered, washed with water, stirred with PE,suction filtered again, washed again with a little PE and dried.

The combined filtrates were evaporated down, dissolved in 50 mL MeOH,combined with 50 mL 4 M NaOH and refluxed for 2 h. MeOH was eliminatedi.vac., the aqueous residue was acidified with conc. HCl andexhaustively extracted with EtOAc. The combined organic phases werewashed with saturated NaCl solution and dried over Na₂SO₄. After thedesiccant and solvent had been eliminated the residue was recrystallisedfrom DCM and combined with the first product fraction.

Yield: 2.02 g (33% of theory)

ESI-MS: (M−H)⁻=211/213 (Cl)

96c (R)-3-(3-chloro-4-methyl-phenyl)-2-hydroxy-propionic acid

Under a nitrogen atmosphere a mixture of 2.6 g (12.23 mmol)3-(3-chloro-4-methyl-phenyl)-2-oxo-propionic acid and 2.1 mL (15.1 mmol)triethylamine in 40 mL THF was cooled to −35° C. Then a solution of 5.87g (18.30 mmol) (1R)-B-chlorodiisopinocampheylborane in 20 mL THF wasadded dropwise so that the reaction temperature remained between −35° C.and −25° C. The cooling bath was removed and the reaction mixture wasstirred overnight at RT. While cooling with ice 30 mL 1 M NaOH and 60 mLdiethyl ether were added dropwise and the mixture was stirred for 15min. The aqueous phase was separated off, the organic phase wasextracted twice with 20 mL 1 M NaOH and once with 20 mL water. Thecombined aqueous phases were acidified with semiconc. HCl while coolingwith ice, extracted twice with 60 mL EtOAc and the combined organicphases were dried over Na₂SO₄. After the desiccant and solvent had beeneliminated the residue was reacted further without purification.

Yield: 2.8 g (85% of theory)

96d methyl (R)-3-(3-chloro-4-methyl-phenyl)-2-hydroxy-propionate

2.0 mL (27.4 mmol) SOCl₂ were slowly added dropwise to a solution of 2.8g (10.4 mmol) of (R)-3-(3-chloro-4-methyl-phenyl)-2-hydroxy-propionicacid in 100 mL MeOH while cooling with ice and the reaction solution wasstirred for 1 h at 0° C. and for 1 h at RT. The reaction mixture wasevaporated down i.vac., the residue was taken up in EtOAc, the organicphase was washed with saturated NaHCO₃ solution and dried over Na₂SO₄.After the desiccant and solvent had been eliminated the residue waspurified by chromatography (silica gel, gradient DCM to DCM/MeOH 50:1).

Yield: 2.12 g (89% of theory)

ESI-MS: (M+H)⁺=229/231 (Cl)

R_(f)=0.34 (Polygram, DCM)

96e (R)-2-(3-chloro-4-methyl-phenyl)-1-methoxycarbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Analogously to Example 31f the desired product was obtained from 2.1 g(9.18 mmol) methyl (R)-3-(3-chloro-4-methyl-phenyl)-2-hydroxy-propionateand 2.45 g (9.99 mmol)3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one.

Yield: 3.4 g (74% of theory)

ESI-MS: (M+H)⁺=500/502 (Cl)

R_(f)=0.52 (Polygram, EtOAc)

96f (R)-1-carboxy-2-(3-chloro-4-methyl-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 0.34 g (14.2 mmol) LiOH in 20 mL water was added to asolution of 3.38 g (6.76 mmol) of(R)-2-(3-chloro-4-methyl-phenyl)-1-methoxycarbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylatein 30 mL THF and the reaction mixture was stirred for 7 h at RT. Themixture was evaporated down i.vac., diluted with 80 mL water, theaqueous phase was extracted twice with 50 mL diethyl ether, the aqueousphase was acidified with 4 M HCl and stirred for 30 min. Theprecipitated product was suction filtered, washed with water and dried.

Yield: 3.2 g (97% of theory)

ESI-MS: (M+H)⁺=486/488 (Cl)

96g(R)-1-(3-chloro-4-methyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 100 mg (0.21 mmol) of(R)-1-carboxy-2-(3-chloro-4-methyl-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,70.0 mg (0.22 mmol) TBTU and 35 μL (0.27 mmol) triethylamine in 10 mLTHF was stirred for 1 h at RT. Then 40 mg (0.22 mmol)1-methyl-4-piperidin-4-yl-piperazine were added and the reaction mixturewas then stirred overnight at RT. The reaction solution was stirred with20 mL semisaturated NaHCO₃ solution, extracted twice with 20 mL EtOAcand the combined organic phases were dried over Na₂SO₄. After thedesiccant and solvent had been eliminated the residue was purified bychromatography (Alox, activity stage II-III DCM/MeOH 40:1).

Yield: 123 mg (83% of theory)

ESI-MS: (M+H)⁺=651/653 (Cl)

R_(f)=0.52 (Polygram-Alox, DCM/MeOH 25:1)

The following compounds were obtained analogously from in each case 100mg (R)-1-carboxy-2-(3-chloro-4-methyl-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand the corresponding amount of amine:

R_(f) Mass (Polygram- Example R Yield (&) spectrum Alox, eluant) 97

74 651/653[M + H]⁺ 0.48DCM/MeOH25:1 98

83 650/652[M + H]⁺ 0.55(DCM/MeOH25:1) 99

74 737/739[M + H]⁺ n.d 100

65 737/739[M + H]⁺ 0.33(DCM/MeOH50:1)

Example 101(R)-1-(3-chloro-4-methyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

10 mL 1 M HCl were added to a solution of 130 mg (0.14 mmol) tert-butyl4-(1-{(R)-3-(3-chloro-4-methyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-piperidin-4-yl)-piperazine-1-carboxylate(Example 99) in 1 mL MeOH and the reaction mixture was stirred for 24 hat RT.

The reaction mixture was freeze-dried directly without any furtherworking up.

The product was obtained as the bis-hydrochloride salt.

Yield: 112 mg (95% of theory)

ESI-MS: (M+H)⁺=637/639 (Cl)

Example 102(R)-1-(3-chloro-4-methyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Analogously to Example 101 the product was obtained from 110 mg (0.13mmol) of(R)-1-(3-chloro-4-methyl-benzyl)-2-[4-(1-tert-butoxy-carbonyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 100), in the form of the bis-hydrochloride salt.

Yield: 99 mg (93% of theory)

ESI-MS: (M+H)⁺=637/639 (Cl)

Example 103(R)-1-(3-bromo-4-methyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

103a (Z,E)-2-acetylamino-3-(3-bromo-4-methyl-phenyl)-acrylic acid

Analogously to Example 1a the product was obtained from 6.0 g (30.1mmol) 3-bromo-4-methyl-benzaldehyde and 5.3 g (45.3 mmol)N-acetylglycine.

Yield: 4.7 g (52% of theory)

ESI-MS: (M+H)⁺=298/300 (Br)

R_(f)=0.12 (silica gel, DCM/MeOH/cyc/NH₃ 70:15:15:2)

103b 3-(3-bromo-4-methyl-phenyl)-2-oxo-propionic acid

28 mL 4 M HCl were added to a solution of 4.7 g (15.8 mmol)(Z,E)-2-acetylamino-3-(3-bromo-4-methyl-phenyl)-acrylic acid in 50 mL1,4-dioxane heated to 105° C. and the reaction mixture was kept for afurther 5 h at this temperature. The 1,4-dioxane was eliminated i.vac.,the cooled residue was combined with water, the precipitate formed wasfiltered off and dried in the circulating air dryer.

Yield: 2.9 g (72% of theory)

ESI-MS: (M−H)⁻=255/257 (Br)

R_(f)=0.18 (silica gel, DCM/MeOH/NH₃ 80:20:2)

103c (R)-3-(3-bromo-4-methyl-phenyl)-2-hydroxy-propionic acid

Under a nitrogen atmosphere a mixture of 2.9 g (11.3 mmol)3-(3-bromo-4-methyl-phenyl)-2-oxo-propionic acid and 2.0 mL (15.1 mmol)triethylamine in 40 mL THF was cooled to −35° C. Then a solution of 5.44g (17.0 mmol) (1R)-B-chlorodiisopinocampheylborane in 20 mL THF wasadded dropwise so that the reaction temperature remained between −35° C.and −25° C.; the reaction mixture was kept for 1 h at this temperature,then the cooling bath was removed and the mixture was stirred overnightat RT. To complete the reaction another 3.0 g (9.4 mmol)(1R)-B-chlorodiisopinocampheylborane were added and the mixture wasstirred for a further 5 h. While cooling with ice 30 mL 1 M NaOH and 30mL TBME were added dropwise and the mixture was stirred for 15 min. Theaqueous phase was separated off, the organic phase was extracted with 15mL 1 M NaOH and 25 mL water. The combined aqueous phases were acidifiedwith 2 M HCl while cooling with ice, extracted three times with 40 mLTBME and the combined organic phases were dried over Na₂SO₄. After thedesiccant and solvent had been eliminated the residue was reactedfurther without purification.

Yield: 3.0 g (approx. 70% proportion of product, 72% of theory)

ESI-MS: (M−H)⁻=257/259 (Br)

R_(f)=0.12 (silica gel, PE/EtOAc 1:1)

103d methyl (R)-3-(3-bromo-4-methyl-phenyl)-2-hydroxy-propionate

A solution of 2.8 g (approx. 70%; 7.56 mmol) of(R)-3-(3-bromo-4-methyl-phenyl)-2-hydroxy-propionic acid in methanolicHCl (1.25 M) was stirred for 4 h at RT. The mixture was evaporated downi.vac. and the residue was purified by chromatography (silica gel,gradient PE/EtOAc 9:1 to PE/EtOAc 1:9).

Yield: 1.6 g (77% of theory)

ESI-MS: (M+H)⁺=273/275 (Br)

R_(f)=0.72 (silica gel, PE/EtOAc 1:1)

103e (R)-2-(3-bromo-4-methyl-phenyl)-1-methoxycarbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Analogously to Example if the crude product was obtained from 1.5 g(5.49 mmol) methyl (R)-3-(3-bromo-4-methyl-phenyl)-2-hydroxy-propionateand 1.7 g (5.52 mmol)4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonylchloride.This was purified by chromatography (silica gel, gradient DCM/MeOH/NH₃100:0:0 to DCM/MeOH/NH₃ 0:95:5). The product fractions were combined,evaporated down i.vac., triturated with DIPE, suction filtered anddried.

Yield: 1.1 g (37% of theory)

ESI-MS: (M+H)⁺=544/546 (Br)

R_(f)=0.70 (silica gel, DCM/MeOH/cyc/NH₃ 70:15:15:2)

103f (R)-2-(3-bromo-4-methyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 70 mg (2.92 mmol) LiOH in 5 mL water was added to asolution of 1.0 g (1.84 mmol) of(R)-2-(3-bromo-4-methyl-phenyl)-1-methoxycarbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylatein 20 mL THF and the reaction mixture was stirred for 5 h at RT. Thereaction solution was evaporated down i.vac., the residue was combinedwith DCM, the organic phase was washed with 1 M KHSO₄ solution and driedover Na₂SO₄.

After the desiccant and solvent had been eliminated the residue wastriturated with DIPE, suction filtered and dried.

Yield: 0.95 g (98% of theory)

ESI-MS: (M+H)⁺=530/532 (Br)

R_(f)=0.29 (silica gel, DCM/MeOH/cyc/NH₃ 70:15:15:2)

103g(R)-1-(3-bromo-4-methyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Analogously to Example 1h the product was obtained from 100 mg (0.19mmol) of (R)-2-(3-bromo-4-methyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand 38 mg (0.21 mmol) 1-methyl-4-piperidin-4-yl-piperazine.

Yield: 90 mg (69% of theory)

ESI-MS: (M+H)⁺=695/697 (Br)

R_(f)=0.59 (silica gel, DCM/MeOH/cyc/NH₃ 70:15:15:2)

The following compounds were obtained analogously from in each case 100mg of (R)-2-(3-bromo-4-methyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand the corresponding amount of amine:

R_(f) (silica gel, eluant) or Mass retention time Example R Yield (%)spectrum HPLC (method) 104

65 695/697[M + H]⁺ 0.58(DCM/MeOH/Cyc/NH₃70:15:15:2) 105

61 694/696[M + H]⁺ 0.57(DCM/MeOH/Cyc/NH₃70:15:15:2) 105

54 781/783[M + H]⁺ 7.1 min(A) 106

61 781/783[M + H]⁺ 6.9 min(A)

Example 107(R)-1-(3-bromo-4-methyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Analogously to Example 93 the product was obtained from 90 mg (0.12mmol) tert-butyl4-(1-{(R)-3-(3-bromo-4-methyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl-oxy]-propionyl}-piperidin-4-yl)-piperazine-1-carboxylate(Example 106).

Yield: 15 mg (19% of theory)

ESI-MS: (M+H)⁺=681/683 (Br)

retention time (HPLC): 5.7 min (method A)

Example 108(R)-1-(3-bromo-4-methyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Analogously to Example 93 the product was obtained from 80 mg (0.12mmol) of(R)-1-(3-bromo-4-methyl-benzyl)-2-[4-(1-tert-butoxy-carbonyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 105).

Yield: 44 mg (63% of theory)

ESI-MS: (M+H)⁺=681/683 (Br)

retention time (HPLC): 5.5 min (method A)

Example 109(R)-1-(6-amino-5-methyl-pyridin-3-ylmethyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

109a methyl(Z,E)-2-acetylamino-3-(6-amino-5-methyl-pyridin-3-yl)-acrylate

Under a nitrogen atmosphere 6.58 g (7.19 mmol)tris-(dibenzylideneacetone)-palladium was added to a mixture of 33.6 g(180 mmol) 5-bromo-3-methyl-pyridin-2-ylamine, 28.9 g (198 mmol) methyl2-acetylamino-acrylate, 4.42 g (14.4 mmol) tri-o-tolyl-phosphane and30.9 mL (180 mmol) ethyldiisopropylamine in 500 mL butyronitrile and thereaction mixture was heated to 110° C. for 17 h. The reaction solutionwas evaporated down i.vac. and the residue was stirred with approx. 500mL water. The precipitate was filtered, recrystallised from acetonitrileand dried.

The aqueous mother liquor was evaporated down and the residue waspurified by chromatography (silica gel, EtOAc/MeOH/NH₃ 90:10:1). Thefractions containing the product were evaporated down, the residue wastriturated with a little acetonitrile, filtered, dried and combined withthe above product fraction.

Yield: 16.6 g (37% of theory)

ESI-MS: (M+H)⁺=250

R_(f)=0.46 (silica gel, EtOAc/MeOH/NH₃ 90:10:1)

109b 3-(6-amino-5-methyl-pyridin-3-yl)-2-oxo-propionic acid

230 mL 4 M HCl were added to a solution of 15.57 g (62.46 mmol) methyl(Z,E)-2-acetylamino-3-(6-amino-5-methyl-pyridin-3-yl)-acrylate in 250 mL1,4-dioxane, the reaction mixture was refluxed for 1.5 h and stirred fora further 16 h at RT. The mixture was evaporated down i.vac., theresidue was triturated with EtOAc/DIPE (1:1), filtered and dried in thecirculating air dryer. The product was obtained as the hydrochloridesalt.

Yield: 14.4 g (100% of theory)

ESI-MS: (M+H)⁺=195

retention time (HPLC): 2.7 min (method A)

109c methyl (R)-3-(6-amino-5-methyl-pyridin-3-yl)-2-hydroxy-propionate

Under an argon atmosphere a mixture of 13.8 g (59.9 mmol)3-(6-amino-5-methyl-pyridin-3-yl)-2-oxo-propionic acid and 17.5 mL(125.7 mmol) triethylamine in 140 mL THF was cooled to −35° C. Then asolution of 40.3 g (126 mmol) (1R)-B-chlorodiisopinocampheylborane in210 mL THF was added dropwise so that the reaction temperature remainedbetween −35° C. and −25° C.; the reaction mixture was kept for 3 h atthis temperature before adding 150 mL 1 M NaOH at 0-5° C. and stirringthe reaction mixture for 2 h at RT. 200 mL TBME were added, the organicphase was separated off and acidified with 200 mL 2 M HCl. The aqueousphase was separated off, evaporated down, the residue was taken up inTHF/MeOH (1:1), filtered and the filtrate was then evaporated down. Thecrude product thus obtained (12.5 g) was dissolved in 300 mL MeOH, 4.3mL (59.3 mmol) SOCl₂ were added dropwise while cooling with ice and themixture was stirred for a further 2 h at RT. It was evaporated downi.vac and the residue was purified by chromatography (silica gel,EtOAc/MeOH/NH₃ 90:10:1).

Yield: 5.62 g (45% of theory)

ESI-MS: (M+H)⁺=211

retention time (HPLC): 2.4 min (method A)

109d (R)-2-(6-amino-5-methyl-pyridin-3-yl)-1-methoxycarbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Analogously to Example 31f the desired product was obtained from 2.75 g(13.10 mmol) methyl(R)-3-(6-amino-5-methyl-pyridin-3-yl)-2-hydroxy-propionate and 3.21 g(13.10 mmol)3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one.

Yield: 1.38 g (22% of theory)

ESI-MS: (M+H)⁺=482

retention time (HPLC): 4.9 min (method C)

109e (R)-2-(6-amino-5-methyl-pyridin-3-yl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 100 mg (4.18 mmol) LiOH in 25 mL water was added to asolution of 1.27 g (2.64 mmol) of(R)-2-(6-amino-5-methyl-pyridin-3-yl)-1-methoxycarbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylatein 30 mL THF and the reaction solution was stirred for 1 h at RT. Themixture was evaporated down i.vac., the residue was taken up in water, 2M KHSO₄ solution were added with stirring, the supernatant solution wasdecanted off, the residue was dried, stirred with THF and the productwas filtered.

Yield: 0.92 g (74% of theory)

ESI-MS: (M+H)⁺=468

retention time (HPLC): 4.8 min (method A)

109f(R)-1-(6-amino-5-methyl-pyridin-3-ylmethyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Analogously to Example 1 h the product was obtained from 50 mg (0.11mmol) of (R)-2-(6-amino-5-methyl-pyridin-3-yl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand 20 mg (0.11 mmol) 1-methyl-4-piperidin-4-yl-piperazine.

Yield: 6 mg (9% of theory)

ESI-MS: (M+H)⁺=633

retention time (HPLC): 4.4 min (method A)

The following compounds were obtained analogously from in each case 50mg (R)-2-(6-amino-5-methyl-pyridin-3-yl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand the corresponding amount of amine:

retention time Mass HPLC Example R Yield (%) spectrum (method) 110

19 633[M + H]⁺ 4.4 min(D) 111

29 632[M + H]⁺ 5.6 min(D) 112

25 618[M + H]⁺ 5.4 min(D) 113

54 719[M + H]⁺ 6.8 min(A) 114

61 719[M + H]⁺ 6.5 min(D)

Example 115(R)-1-(6-amino-5-methyl-pyridin-3-ylmethyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 75 mg (0.10 mmol) of tert-butyl4-(1-{(R)-3-(6-amino-5-methyl-pyridin-3-yl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-yl}-piperidin-4-yl)-piperazine-1-carboxylate(Example 114) in 5 mL 2 M HCl was stirred for 20 h at RT. Afterlyophilisation of the reaction mixture the residue was dissolved in 1 mLDMF, made alkaline with 0.6 mL saturated K₂CO₃ solution and purified byHPLC. The fractions containing the product were combined and againlyophilised.

Yield: 28 mg (44% of theory)

ESI-MS: (M+H)⁺=619

retention time (HPLC): 3.8 min (method A)

Example 116(R)-1-(6-amino-5-methyl-pyridin-3-ylmethyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Analogously to Example 115 the product was obtained from 66 mg (0.09mmol) of(R)-1-(6-amino-5-methyl-pyridin-3-ylmethyl)-2-[4-(1-tert-butoxy-carbonyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 113).

Yield: 29 mg (51% of theory)

ESI-MS: (M+H)⁺=619

retention time (HPLC): 3.5 min (method A)

Example 117(R)-1-(4-hydroxy-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

117a (Z,E)-2-acetylamino-3-(4-benzyloxy-phenyl)-acrylic acid

Analogously to Example 1a the product was obtained from 30.0 g (141mmol) 4-benzyloxy-benzaldehyde and 24.8 g (212 mmol) N-acetyl-glycine.

Yield: 32.0 g (73% of theory)

ESI-MS: (M+H)⁺=312

R_(f)=0.35 (silica gel, DCM/MeOH/AcOH 90:10:1)

117b 3-(4-benzyloxy-phenyl)-2-oxo-propionic acid

Analogously to Example 1b the product was obtained from 32.0 g (103mmol) (Z,E)-2-acetylamino-3-(4-benzyloxy-phenyl)-acrylic acid.

Yield: 12.4 g (45% of theory)

ESI-MS: (M−H)⁻=269

R_(f)=0.30 (silica gel, DCM/MeOH/AcOH 80:20:2)

117c (R)-3-(4-benzyloxy-phenyl)-2-hydroxy-propionic acid

Analogously to Example 1c the product was obtained from 11.5 g (42.6mmol) 3-(4-benzyloxy-phenyl)-2-oxo-propionic acid and 16.7 g (52.1 mmol)(1R)-B-chlorodiisopinocampheylborane.

Yield: 7.43 g (64% of theory)

ESI-MS: (M+Na)⁺=294

retention time (HPLC): 13.3 min (method F)

117d methyl (R)-3-(4-benzyloxy-phenyl)-2-hydroxy-propionate

Analogously to Example 46d the product was obtained from 7.3 g (26.8mmol) of (R)-3-(4-benzyloxy-phenyl)-2-hydroxy-propionic acid.

Yield: 7.6 g (99% of theory)

retention time (HPLC): 16.7 min (method F)

117e (R)-2-(4-benzyloxy-phenyl)-1-methoxycarbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Analogously to Example 31f the product was obtained from 7.6 g (26.5mmol) of methyl (R)-3-(4-benzyloxy-phenyl)-2-hydroxy-propionate and 6.5g (26.5 mmol)3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one.

Yield: 4.1 g (28% of theory)

ESI-MS: (M+H)⁺=558

R_(f)=0.25 (silica gel, n-hexane/EtOAc 3:7)

retention time (HPLC): 22.0 min (method F)

117f (R)-1-carboxy-2-(4-benzyloxy-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Analogously to Example 58f the product was obtained from 4.1 g (7.4mmol) of (R)-2-(4-benzyloxy-phenyl)-1-methoxy-carbonyl-ethyl(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand 264 mg (11.0 mmol) LiOH.

Yield: 2.7 g (68% of theory)

ESI-MS: (M+H)⁺=544

retention time (HPLC): 18.8 min (method F)

117g (R)-1-carboxy-2-(4-hydroxy-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

220 mg 10% Pd/C were added to a solution of 2.2 g (4.1 mmol) of(R)-1-carboxy-2-(4-benzyloxy-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand 450 mg (4.4 mmol) triethylamine in 90 mL MeOH and the reactionmixture was hydrogenated at 3 bar H₂ for 24 h. The catalyst wasfiltered, washed twice with MeOH and the filtrate was evaporated downi.vac. The residue was taken up in 20 mL water and adjusted to pH 2-3with 10% HCl. The precipitate formed was filtered, washed with a littlewater and dried at 50° C.

Yield: 1.4 g (76% of theory)

ESI-MS: (M+H)⁺=454

R_(f)=0.65 (silica gel, DCM/MeOH/AcOH 80:20:2)

117h(R)-1-(4-hydroxy-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Under a nitrogen atmosphere 74 mg (0.40 mmol)1-methyl-4-piperidin-4-yl-piperazine was added to a solution of 140 mg(0.31 mmol) of (R)-1-carboxy-2-(4-hydroxy-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,150 mg (0.39 mmol) HATU and 80 μL (0.47 mmol) ethyldiisopropylamine in 5mL DMF and the reaction mixture was stirred for 6 h at RT. The reactionsolution was evaporated down i.vac. and the residue was purified bychromatography (silica gel, DCM/MeOH/NH₃ 93:7:0.7).

Yield: 100 mg (52% of theory)

ESI-MS: (M+H)⁺=619

R_(f)=0.6 (silica gel, DCM/MeOH/NH₃ 80:20:2)

The following compounds were obtained analogously from in each case 140mg (Examples 118 and 119),150 mg (Examples 120 and 121), 200 mg(Examples 122 and 123) or 230 mg (Example 124) of(R)-1-carboxy-2-(4-hydroxy-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand the corresponding amount of amine:

R_(f) Mass (silica gel, Example R Yield (%) spectrum eluant) 118

27 604[M + H]⁺ 0.70(DCM/MeOH/NH₃80:20:2) 119

47 618[M + H]⁺ 0.65(DCM/MeOH/NH₃80:20:2) 120

64 619[M + H]⁺ 0.35(DCM/MeOH/NH₃80:20:2) 121

54 564[M + H]⁺ 0.40(DCM/MeOH/NH₃80:20:2) 122

45 704[M + H]⁺ 0.65(DCM/MeOH/NH₃80:20:2) 123

43 827[M + H]⁺ 0.40(DCM/MeOH/AcOH90:10:1) 124

53 705[M + H]⁺ 0.65(DCM/MeOH/NH₃80:20:2)

Example 125(R)-1-(4-hydroxy-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 250 mg (0.30 mmol) 9H-fluoren-9-ylmethyl4-(1-{(R)-3-(4-hydroxy-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-piperidin-4-yl)-piperazine-1-carboxylate(Example 123) in 4 mL piperidine was stirred for 30 min at RT. Thereaction mixture was evaporated down i.vac. and the residue was purifiedby chromatography (silica gel, DCM/MeOH/NH₃ 90:10:1).

Yield: 40 mg (22% of theory)

ESI-MS: (M+H)⁺=605

retention time (HPLC): 4.7 min (method F)

Example 126(R)-1-(4-hydroxy-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

To a solution of 210 mg (0.30 mmol) of(R)-1-(4-hydroxy-benzyl)-2-[4-(1-tert-butoxy-carbonyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 124) in 1.5 mL formic acid was stirred for 3 h at RT. Thereaction mixture was evaporated down i.vac. and the residue was purifiedby chromatography (silica gel, DCM/MeOH/NH₃ 90:10:1).

Yield: 40 mg (22% of theory)

ESI-MS: (M+H)⁺=605

R_(f)=0.45 (silica gel, DCM/MeOH/NH₃ 80:20:2)

retention time (HPLC): 4.6 min (method F)

Example 127(R)-2-(4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Analogously to Example 126 the product was obtained from 130 mg (0.19mmol) of tert-butyl1′-{(R)-3-(4-hydroxy-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-4,4′-bipiperidinyl-1-carboxylate(Example 122).

Yield: 70 mg (63% of theory)

ESI-MS: (M+H)⁺=604

R_(f)=0.20 (silica gel, DCM/MeOH/NH₃ 80:20:2)

retention time (HPLC): 6.9 min (method F)

Example 128(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

128a (Z,E)-3-(4-acetoxy-3,5-dibromo-phenyl)-2-acetylamino-acrylic acid

Analogously to Example 1a the product was obtained from 30 g (107 mmol)3,5-dibromo-4-hydroxy-benzaldehyde and 18.8 g (161 mmol)N-acetyl-glycine.

Yield: 35.7 g (79% of theory)

ESI-MS: (M+H)⁺=420/422/424 (2 Br)

R_(f)=0.20 (silica gel, DCM/MeOH/AcOH 90:10:1)

128b 3-(3,5-dibromo-4-hydroxy-phenyl)-2-oxo-propionic acid

Analogously to Example 1b the product was obtained from 35.7 g (84.8mmol) (Z,E)-3-(4-acetoxy-3,5-dibromo-phenyl)-2-acetylamino-acrylic acid.

Yield: 20.5 g (72% of theory)

ESI-MS: (M−H)⁻=335/337/339 (2 Br)

R_(f)=0.35 (silica gel, DCM/MeOH/AcOH 80:20:2)

128c (R)-3-(3,5-dibromo-4-hydroxy-phenyl)-2-hydroxy-propionic acid

Analogously to Example 1c the product was obtained from 14.5 g (42.9mmol) 3-(3,5-dibromo-4-hydroxy-phenyl)-2-oxo-propionic acid and 30.9 g(96.33 mmol) (1R)-B-chlorodiisopinocampheylborane.

Yield: 12.7 g (87% of theory)

ESI-MS: (M−H)⁻=337/339/341 (2 Br)

R_(f)=0.4 (silica gel, DCM/MeOH/AcOH 80:20:2)

retention time (HPLC): 6.4 min (method F)

128d methyl (R)-3-(3,5-dibromo-4-hydroxy-phenyl)-2-hydroxy-propionate

Analogously to Example 46d the product was obtained from 14.0 g (34.8mmol) 3(R)-3-(3,5-dibromo-4-hydroxy-phenyl)-2-hydroxy-propionic acid.

Yield: 7.0 g (57% of theory)

ESI-MS: (M−H)⁻=351/353/355 (2 Br)

retention time (HPLC): 9.8 min (method F)

128e methyl(R)-3-[3,5-dibromo-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-2-hydroxy-propionate

Under a nitrogen atmosphere 11.1 g (76.6 mmol) 40% KF/Al₂O₃ were addedto a solution of 6.78 g (19.2 mmol) methyl(R)-3-(3,5-dibromo-4-hydroxy-phenyl)-2-hydroxy-propionate in 100 mLacetonitrile and the resulting suspension was stirred for a few minutesat RT. Subsequently a solution of 4.07 mL (23.0 mmol)(2-chloromethoxy-ethyl)-trimethyl-silane in 20 mL acetonitrile was addedand the reaction mixture was stirred for 20 h at RT. The mixture wasfiltered through Celite, the solvent was evaporated down i.vac. and theresidue was purified by chromatography (silica gel, n-hexane/EtOAc 7:3).

Yield: 5.49 g (59% of theory)

R_(f)=0.45 (silica gel, n-hexane/EtOAc 1:1)

128f(R)-2-[3,5-dibromo-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-methoxy-carbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Analogously to Example 31f the product was obtained from 4.63 g (9.56mmol) methyl(R)-3-[3,5-dibromo-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-2-hydroxy-propionateand 2.35 g (9.56 mmol)3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one.

Yield: 4.35 g (69% of theory)

ESI-MS: (M+H)⁺=754/756/758 (2 Br)

retention time (HPLC): 29.2 min (method F)

128g (R)-2-(3,5-dibromo-4-hydroxy-phenyl)-1-methoxycarbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Under a nitrogen atmosphere 5.46 mL methanolic H₂SO₄ (0.5 M) were addedto a solution of 4.30 g (5.69 mmol) of(R)-2-[3,5-dibromo-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-methoxy-carbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylatein 40 mL THF and 40 mL MeOH and the reaction solution was stirred for 6h at RT. The reaction mixture was evaporated down i.vac and the residuewas reacted further without purification.

Yield: quantitative

ESI-MS: (M+H)⁺=624/626/628 (2 Br)

retention time (HPLC): 17.3 min (method F)

128h (R)-1-carboxy-2-(3,5-dibromo-4-hydroxy-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 0.51 g (21.3 mmol) LiOH was added to a solution of(R)-2-(3,5-dibromo-4-hydroxy-phenyl)-1-methoxycarbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(crude product from Example 128g) in 80 mL THF and the reaction mixturewas stirred for 3 h at RT. The THF was eliminated i. vac., the aqueousphase was washed with EtOAc, acidified with 10% HCl and the aqueousphase was extracted exhaustively with EtOAc. The combined organic phaseswere evaporated down i.vac., suspended in diethyl ether, filtered, theresidue was dried and then purified by chromatography (silica gel,DCM/MeOH/AcOH 90:10:1).

Yield: 3.5 g (100% of theory)

ESI-MS: (M+H)⁺=610/612/614 (2 Br)

retention time (HPLC): 14.1 min (method F)

128i(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Under a nitrogen atmosphere 55 mg (0.30 mmol)1-methyl-4-piperidin-4-yl-piperazine was added to a solution of 151 mg(0.25 mmol) of (R)-1-carboxy-2-(3,5-dibromo-4-hydroxy-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,104 mg (0.27 mmol) HATU and 47 μL (0.27 mmol) ethyldiisopropylamine in 5mL DMF and the reaction mixture was stirred for 3 h at RT. The reactionsolution was evaporated down i.vac. and the residue was purified bychromatography (silica gel, DCM/MeOH/NH₃ 80:20:2).

Yield: 190 mg (99% of theory)

ESI-MS: (M+H)⁺=775/777/779 (2 Br)

R_(f)=0.3 (silica gel, DCM/MeOH/AcOH 80:20:2)

retention time (HPLC): 7.2 min (method F)

The following compounds were obtained analogously from in each case 151mg (R)-1-carboxy-2-(3,5-dibromo-4-hydroxy-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand the corresponding amount of amine:

retention time Mass HPLC Example R Yield (%) spectrum (method) 129

95 760/762/764[M + H]⁺ 9.5 min(F) 130

89 775/777/779[M + H]⁺ 6.7 min(F) 131

93 774/776/778[M + H]⁺ 9.6 min(F) 132

82 720/722/724[M + H]⁺ 8.7 min(F) 133

91 761/763/765[M + H − Fmoc]⁺ 15.0 min (F)

Example 134(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Analogously to Example 128i the crude product was obtained from 200 mg(0.33 mmol) of (R)-1-carboxy-2-(3,5-dibromo-4-hydroxy-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,140 μL (0.82 mmol) ethyldiisopropylamine and 135 mg (0.44 mmol)tert-butyl 4-piperazin-1-yl-piperidine-1-carboxylate (used as thehydrochloride salt). This product was dissolved in 2 mL formic acid andstirred for 2 h at RT. The reaction mixture was evaporated down i.vac.and the residue was purified by chromatography (silica gel, elutingfirst with DCM/MeOH/NH₃ 80:20:2 then with DCM/MeOH/NH₃ 50:50:5).

Yield: 20 mg (8% of theory)

ESI-MS: (M+H)⁺=761/763/765 (2 Br)

R_(f)=0.35 (silica gel, DCM/MeOH/NH₃ 80:20:2)

retention time (HPLC): 6.5 min (method F)

Example 135(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 200 mg (0.20 mmol) 9H-fluoren-9-ylmethyl4-(1-{(R)-3-(3,5-dibromo-4-hydroxy-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-piperidin-4-yl)-piperazine-1-carboxylate(Example 133) in 4 mL piperidine was stirred for 30 min at RT. Thereaction mixture was evaporated down i.vac. and the residue was purifiedby chromatography (silica gel, DCM/MeOH/NH₃ 80:20:2).

Yield: 20 mg (8% of theory)

ESI-MS: (M+H)⁺=761/763/765 (2 Br)

retention time (HPLC): 6.8 min (method F)

Example 136(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-(1′-methanesulphonyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 130 mg (0.21 mmol) of(R)-1-carboxy-2-(3,5-dibromo-4-hydroxy-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,80 mg (0.25 mmol) TBTU and 50 μL (0.27 mmol) ethyldiisopropylamine in 10mL THF was stirred for 50 min at RT. Then 60 mg (0.24 mmol)1-methanesulphonyl-[4,4′]bipiperidinyl were added and the reactionmixture was stirred overnight at RT. The reaction solution was dilutedwith 50 mL EtOAc, extracted twice with 30 mL 15% K₂CO₃ solution, theorganic phase was separated off and dried over MgSO₄. After thedesiccant and solvent had been eliminated the residue was trituratedwith water and filtered. The solid was combined with 5 mL 1 M HCl andstirred overnight. Further purification of the crude product was carriedout by chromatography (silica gel, gradient DCM to DCM/MeOH/NH₃50:45:5). The fractions containing the product were combined, evaporateddown i.vac., triturated with DIPE, suction filtered and dried at 40° C.

Yield: 80 mg (45% of theory)

ESI-MS: (M+H)⁺=838/840/842 (2 Br)

R_(f)=0.42 (silica gel, DCM/MeOH/cyc/NH₃ 70:15:15:2)

Example 137(R)-2-(4-amino-4-methyl-1,4′-bipiperidinyl-1′-yl)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Analogously to Example 1h the product was obtained from 80 mg (0.13mmol) of (R)-1-carboxy-2-(3,5-dibromo-4-hydroxy-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand 36 mg (0.14 mmol) 4-methyl-[1,4′]bipiperidinyl-4-ylamine (used asthe bis-hydrochloride salt), being obtained as the formate salt.

Yield: 6 mg (6% of theory)

ESI-MS: (M+H)⁺=789/791/793 (2 Br)

retention time (HPLC): 4.9 min (method A)

Example 138(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

208 mg (0.82 mmol) ethyl [4,4′]bipiperidinyl-1-yl-acetate were added toa solution of 500 mg (0.82 mmol) of(R)-1-carboxy-2-(3,5-dibromo-4-hydroxy-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,315 mg (0.98 mmol) TBTU and 150 μL (1.06 mmol) triethylamine in 5 mL DMFand the reaction mixture was stirred overnight at RT. To complete thereaction a further 315 mg (0.98 mmol) TBTU, 150 μL (1.06 mmol)triethylamine and 208 mg (0.82 mmol) ethyl[4,4′]bipiperidinyl-1-yl-acetate were added and the mixture was againstirred overnight at RT. The reaction mixture was purified directly byHPLC without any further working up. The fractions containing theproduct were combined, evaporated down i.vac., neutralised withsaturated NaHCO₃ solution, the aqueous phase was extracted twice with100 mL DCM and the combined organic phases were dried over Na₂SO₄. Afterthe desiccant and solvent had been eliminated the residue was trituratedwith DIPE, suction filtered and dried in the air.

Yield: 204 mg (29% of theory)

ESI-MS: (M+H)⁺=846/848/850 (2 Br)

retention time (HPLC): 6.5 min (method A)

Example 139(R)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 1.4 mg (0.06 mmol) LiOH in 1 mL water was added to asolution of 30 mg (0.04 mmol) of(R)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 138) in 3 mL THF and the reaction solution was stirredovernight at RT. The solvent was eliminated in the nitrogen current, theresidue was taken up in 1 mL water, acidified with formic acid, theprecipitate formed was removed by suction filtering and dried in vacuo.

Yield: 20 mg (69% of theory)

ESI-MS: (M+H)⁺=818/820/822 (2 Br)

retention time (HPLC): 6.5 min (method A)

Example 140(R)-2-(4-amino-4-methyl-1,4′-bipiperidinyl-1′-yl)-1-(3,5-bis-trifluoromethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Analogously to Example 1h the product was obtained from 80 mg (0.14mmol) of (R)-2-(3,5-bis-trifluoromethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 46f) and 38 mg (0.14 mmol)4-methyl-[1,4′]bipiperidinyl-4-ylamine (used as the bis-hydrochloridesalt), in the form of the formate salt.

Yield: 47 mg (42% of theory)

ESI-MS: (M+H)⁺=753

retention time (HPLC): 5.4 min (method A)

Example 141(R)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Analogously to Example 46g the product was obtained from 200 mg (0.42mmol) of (R)-1-carboxy-2-(4-hydroxy-3,5-dimethyl-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 69h) and 117 mg (0.46 mmol)ethyl[4,4′]bipiperidinyl-1-yl-acetate.

Yield: 222 mg (74% of theory)

ESI-MS: (M+H)⁺=718

retention time (HPLC): 3.1 min (method E)

Example 142(R)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Analogously to Example 139 the product was obtained from 100 mg (0.14mmol) of(R)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 141) and 3.8 mg (0.16 mmol) LiOH.

Yield: 56 mg (58% of theory)

ESI-MS: (M−H)⁻=688

retention time (HPLC): 3.0 min (method E)

Example 143(R)-2-(4-cyclohexyl-piperazin-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Analogously to Example 1h the product was obtained from 69 mg (0.14mmol) of (R)-1-carboxy-2-(4-hydroxy-3,5-dimethyl-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 69h) and 24 mg (0.14 mmol) 1-cyclohexyl-piperazine.

Yield: 51 mg (91% of theory)

ESI-MS: (M+H)⁺=632

retention time (HPLC): 3.1 min (method E)

Example 144(R)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-1-(3-trifluoromethyl-benzyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

144a (Z,E)-2-acetylamino-3-(3-trifluoromethyl-phenyl)-acrylic acid

Analogously to Example 1a the product was obtained from 15.8 g (115mmol) 3-trifluoromethyl-benzaldehyde and 21.3 g (182 mmol)N-acetyl-glycine.

Yield: 16.7 g (53% of theory)

ESI-MS: (M+H)⁺=274

R_(f)=0.4 (silica gel, DCM/MeOH/AcOH 90:10:1)

144b 2-oxo-3-(3-trifluoromethyl-phenyl)-propionic acid

Analogously to Example 46b the product was obtained from 16.6 g (60.8mmol) (Z,E)-2-acetylamino-3-(3-trifluoromethyl-phenyl)-acrylic acid.

Yield: 5.7 g (40% of theory)

ESI-MS: (M−H)⁻=231

R_(f)=0.19 (silica gel, DCM/MeOH/cyc/NH₃ 70:15:15:2)

144c (R)-2-hydroxy-3-(3-trifluoromethyl-phenyl)-propionic acid

Analogously to Example 1c the product was obtained from 5.70 g (24.6mmol) 2-oxo-3-(3-trifluoromethyl-phenyl)-propionic acid and 11.8 g (36.8mmol) (1 R)-B-chlorodiisopinocampheylborane.

Yield: 4.25 g (74% of theory)

ESI-MS: (M−H)⁻=233

R_(f)=0.35 (silica gel, DCM/MeOH/cyc/NH₃ 70:15:15:2)

144d methyl (R)-2-hydroxy-3-(3-trifluoromethyl-phenyl)-propionate

Analogously to Example 46d the product was obtained from 4.20 g (17.9mmol) of (R)-2-hydroxy-3-(3-trifluoromethyl-phenyl)-propionic acid.

Yield: 2.47 g (55% of theory)

ESI-MS: (M+H)⁺=249

R_(f)=0.73 (silica gel, DCM/MeOH/cyc/NH₃ 70:15:15:2)

144e (R)-1-methoxycarbonyl-2-(3-trifluoromethyl-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Analogously to Example 31f the product was obtained from 2.47 g (9.95mmol) methyl (R)-2-hydroxy-3-(3-trifluoromethyl-phenyl)-propionate and4.10 g (65% purity, 10.9 mmol)3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one.

Yield: 3.16 g (61% of theory)

ESI-MS: (M+H)⁺=520

R_(f)=0.93 (silica gel, EtOAc/MeOH/NH₃ 80:20:2)

144f (R)-1-carboxy-2-(3-trifluoromethyl-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Analogously to Example 46f the product was obtained from 3.10 g (5.97mmol) of (R)-1-methoxycarbonyl-2-(3-trifluoro-methyl-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand 0.22 g (9.00 mmol) LiOH.

Yield: 2.80 g (93% of theory)

ESI-MS: (M+H)⁺=506

R_(f)=0.58 (silica gel, EtOAc/MeOH/NH₃ 70:30:3)

144g(R)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-1-(3-trifluoromethyl-benzyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-l-carboxylate

Analogously to Example 1h the product was obtained from 80.0 mg (0.16mmol) of (R)-1-carboxy-2-(3-trifluoromethyl-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand 29.6 mg (0.16 mmol) 1-methyl-4-piperidin-4-yl-piperazine.

Yield: 67 mg (63% of theory)

ESI-MS: (M+H)⁺=671

R_(f)=0.4 (silica gel, DCM/MeOH/cyc/NH₃ 70:15:15:2)

The following compounds were obtained analogously from in each case 80mg (Examples 145 to 148) or 140 mg (Examples 149 and 150) of(R)-1-carboxy-2-(3-trifluoro-methyl-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand the corresponding amount of amine:

R_(f) (silica gel, DCM/MeOH/cyc/NH₃ 70:15:15:2) or Mass retention timeExample R Yield (%) spectrum HPLC (method) 145

93 656[M + H]⁺ 0.68 146

64 671[M + H]⁺ 0.35 147

74 670[M + H]⁺ 0.53 148

48 685[M + H]⁺ 5.1 min(A) 149

62 757[M + H]⁺ 0.51 150

71 757[M + H]⁺ 0.50

Example 151(R)-1-(3-methyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 131 mg (0.17 mmol) tert-butyl4-{1-[(R)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-3-(3-trifluoromethyl-phenyl)-propionyl]-piperidin-4-yl}-piperazine-1-carboxylate(Example 149) in 1.5 mL of 4 M HCl was stirred overnight at RT. Thereaction solution was purified by HPLC without any further working up.The fractions containing the product were combined and lyophilised.

Yield: 75 mg (67% of theory)

ESI-MS: (M+H)⁺=657

R_(f)=0.38 (silica gel, DCM/MeOH/cyc/NH₃ 70:15:15:2)

Example 152(R)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-1-(3-trifluoromethyl-benzyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Analogously to Example 151 the product was obtained from 149 mg (0.20mmol) of(R)-1-(3-trifluoromethyl-benzyl)-2-[4-(1-tert-butoxy-carbonyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 150).

Yield: 66 mg (51% of theory)

ESI-MS: (M+H)⁺=657

R_(f)=0.18 (silica gel, DCM/MeOH/cyc/NH₃ 70:15:15:2)

Example 153(R)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-1-(3-methyl-benzyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

153a (Z,E)-2-acetylamino-3-m-tolyl-acrylic acid

Analogously to Example 1a the product was obtained from 25.0 g (212mmol) 3-methyl-benzaldehyde and 24.9 g (212 mmol) N-acetyl-glycine.

Yield: 26.0 g (56% of theory)

ESI-MS: (M+H)⁺=220

retention time (HPLC): 5.4 min (method A)

153b 2-oxo-3-m-tolyl-propionic acid

Analogously to Example 46b the product was obtained from 13.0 g (59.3mmol) (Z,E)-2-acetylamino-3-m-tolyl-acrylic acid.

Yield: 9.2 g (88% of theory)

ESI-MS: (M−H)⁻=177

retention time (HPLC): 7.3 min (method A)

153c (R)-2-hydroxy-3-m-tolyl-propionic acid

Analogously to Example 1c the product was obtained from 9.24 g (51.9mmol) of 2-oxo-3-m-tolyl-propionic acid and 24.0 g (74.8 mmol)(1R)-B-chlorodiisopino-campheylborane.

Yield: 8.4 g (90% of theory)

ESI-MS: (M−H)⁻=179

retention time (HPLC): 7.2 min (method A)

153d methyl (R)-2-hydroxy-3-m-tolyl-propionate

Analogously to Example 31 e the product was obtained from 8.40 g (46.6mmol) of (R)-2-hydroxy-3-m-tolyl-propionic acid and 3.74 mL (51.28 mmol)SOCl₂.

Yield: 6.28 g (69% of theory)

ESI-MS: (M+H)⁺=195

retention time (HPLC): 6.9 min (method A)

153e (R)-1-methoxycarbonyl-2-m-tolyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Analogously to Example 31f the product was obtained from 1.12 g (5.76mmol) methyl (R)-2-hydroxy-3-m-tolyl-propionate and 1.41 g (5.76 mmol)3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one.

Yield: 2.07 g (77% of theory)

ESI-MS: (M+H)⁺=466

retention time (HPLC): 9.0 min (method A)

153f (R)-1-carboxy-2-m-tolyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Analogously to Example 46f the product was obtained from 2.07 g (4.45mmol) of (R)-1-methoxycarbonyl-2-m-tolyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand 0.16 g (6.72 mmol) LiOH.

Yield: 1.86 g (93% of theory)

ESI-MS: (M+H)⁺=452

retention time (HPLC): 8.0 min (method A)

153g(R)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-1-(3-methyl-benzyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Analogously to Example 1h the product was obtained from 80.0 mg (0.18mmol) of (R)-1-carboxy-2-m-tolyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand 33.1 mg (0.18 mmol) 1-methyl-4-piperidin-4-yl-piperazine.

Yield: 46.7 mg (43% of theory)

ESI-MS: (M+H)⁺=617

retention time (HPLC): 5.5 min (method A)

The following compounds were obtained analogously from in each case 80mg of (R)-1-carboxy-2-m-tolyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand the corresponding amount of amine:

retention time Mass HPLC Example R Yield (%) spectrum (method) 154

80 617[M + H]⁺ 5.0 min(A) 155

75 616[M + H]⁺ 6.2 min(A)

The following Examples describe the preparation of pharmaceuticalformulations which contain as active substance any desired compound ofgeneral formula (I):

Example I Capsules for Powder Inhalation Containing 1 mg of ActiveIngredient

Composition:

1 capsule for powder inhalation contains: active ingredient 1.0 mglactose 20.0 mg hard gelatine capsules 50.0 mg 71.0 mg

Method of Preparation:

The active ingredient is ground to the particle size required forinhaled substances. The ground active ingredient is homogeneously mixedwith the lactose. The mixture is transferred into hard gelatinecapsules.

Example II Inhalable Solution for Respimat® Containing 1 mg of ActiveIngredient

Composition:

1 puff contains: active ingredient 1.0 mg benzalkonium chloride 0.002 mgdisodium edetate 0.0075 mg purified water ad 15.0 μl

Method of Preparation:

The active ingredient and benzalkonium chloride are dissolved in waterand transferred into Respimat® cartridges.

Example III Inhalable Solution for Nebulisers Containing 1 mg of ActiveIngredient

Composition:

1 vial contains: active ingredient 0.1 g sodium chloride 0.18 gbenzalkonium chloride 0.002 g purified water ad 20.0 ml

Method of Preparation:

The active ingredient, sodium chloride and benzalkonium chloride aredissolved in water.

Example IV Propellant Gas-Operated Metering Aerosol Containing 1 mg ofActive Ingredient

Composition:

1 puff contains: active ingredient 1.0 mg lecithin 0.1% propellant gasad 50.0 μl

Method of Preparation:

The micronised active ingredient is homogeneously suspended in themixture of lecithin and propellant gas. The suspension is transferredinto a pressurised container with a metering valve.

Example V Nasal Spray Containing 1 mg of Active Ingredient

Composition:

active ingredient 1.0 mg sodium chloride 0.9 mg benzalkonium chloride0.025 mg disodium edetate 0.05 mg purified water ad 0.1 ml

Method of Preparation:

The active ingredient and the excipients are dissolved in water andtransferred into a suitable container.

Example VI Injectable Solution Containing 5 mg of Active Substance per 5ml

Composition:

active substance 5 mg glucose 250 mg human serum albumin 10 mgglycofurol 250 mg water for injections ad 5 ml

Preparation:

Glycofurol and glucose are dissolved in water for injections (WfI);human serum albumin is added; active ingredient is dissolved withheating; made up to specified volume with WfI; transferred into ampoulesunder nitrogen gas.

Example VII Injectable Solution Containing 100 mg of Active Substanceper 20 ml

Composition:

active substance 100 mg monopotassium dihydrogen phosphate = KH₂PO₄ 12mg disodium hydrogen phosphate = Na₂HPO₄.2H₂O 2 mg sodium chloride 180mg human serum albumin 50 mg Polysorbate 80 20 mg water for injectionsad 20 ml

Preparation:

Polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate anddisodium hydrogen phosphate are dissolved in water for injections (WfI);human serum albumin is added; active ingredient is dissolved withheating; made up to specified volume with WfI; transferred intoampoules.

Example VIII Lyophilisate Containing 10 mg of Active Substance

Composition:

Active substance 10 mg Mannitol 300 mg human serum albumin 20 mg waterfor injections ad 2 ml

Preparation:

Mannitol is dissolved in water for injections (WfI); human serum albuminis added; active ingredient is dissolved with heating; made up tospecified volume with WfI; transferred into vials; freeze-dried.

Solvent for lyophilisate:

Polysorbate 80 = Tween 80 20 mg mannitol 200 mg water for injections ad10 ml

Preparation:

Polysorbate 80 and mannitol are dissolved in water for injections (WfI);transferred into ampoules.

Example IX Tablets Containing 20 mg of Active Substance

Composition:

active substance 20 mg lactose 120 mg maize starch 40 mg magnesiumstearate 2 mg Povidone K 25 18 mg

Preparation:

Active substance, lactose and maize starch are homogeneously mixed;granulated with an aqueous solution of Povidone; mixed with magnesiumstearate; compressed in a tablet press; weight of tablet 200 mg.

Example X Capsules Containing 20 mg Active Substance

Composition:

active substance 20 mg maize starch 80 mg highly dispersed silica  5 mgmagnesium stearate 2.5 mg 

Preparation:

Active substance, maize starch and silica are homogeneously mixed; mixedwith magnesium stearate; the mixture is packed into size for 3 hardgelatine capsules in a capsule filling machine.

Example XI Suppositories Containing 50 mg of Active Substance

Composition:

active substance  50 mg hard fat (Adeps solidus) q.s. ad 1700 mg

Preparation:

Hard fat is melted at about 38° C.; ground active substance ishomogeneously dispersed in the molten hard fat; after cooling to about35° C. it is poured into chilled moulds.

Example XII Injectable Solution Containing 10 mg of Active Substance per1 ml

Composition:

active substance 10 mg mannitol 50 mg human serum albumin 10 mg waterfor injections ad 1 ml

Preparation:

Mannitol is dissolved in water for injections (WfI); human serum albuminis added; active ingredient is dissolved with heating; made up tospecified volume with WfI; transferred into ampoules under nitrogen gas.

1. A compound selected from the group consisting of: Com- pound No.Structure (529)

(535)

or a tautomer or salt thereof.
 2. The compound, in accordance with claim1, having the following structure: Compound No. Structure (529)

or a tautomer or salt thereof.
 3. The compound, in accordance with claim1, having the following structure: Compound No. Structure (535)

or a tautomer or salt thereof.
 4. A physiologically acceptable salt of acompound according to claim 1, 2 or
 3. 5. A pharmaceutical compositioncontaining a compound according to claim 1, 2 or 3, or a physiologicallyacceptable salt thereof together with one or more inert carriers and/ordiluents.
 6. A method for treating migraine or cluster headaches whichcomprises administering to a host suffering from the same atherapeutically effective amount of a compound of the formula I inaccordance with claim 1, 2, or 3, or tautomer or physiologicallyacceptable salt thereof.